Pyrimidine compounds and methods using the same

ABSTRACT

The present invention relates to 2-amino-4-arylpyrimidine and 2-amino-4-aryltriazine compounds as inhibitors of heat shock protein 90 family of chaperone proteins. The invention also features pharmaceutical compositions and kits that include the compounds and compositions of the invention. The invention further relates to the medical use of these compounds and compositions for the treatment of a disorder hi a subject. For example, the disorder is a neurodegenerative disease.

STATEMENT AS TO FEDERALLY FUNDED RESEARCH

This invention was made with government support under Grant No. STTR1R41G042205-01 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

In general, the present invention relates to pyrimidine-based smallmolecule inhibitors of heat shock protein 90 (Hsp90) and pharmaceuticalcompositions thereof. The invention further relates to methods oftreatment of a subject having a neurodegenerative disease.

BACKGROUND OF THE INVENTION

Hsp90 proteins are implicated in stabilizing protein conformations,maintaining the function of many cell-signaling proteins, and ATPaseactivity. Hsp90 activity is also required for the proper folding,stabilization, activation, and localization of oncoproteins involved intumor progression. The N-terminus ATP binding domain is responsible forthe ATPase activity of this protein: this adenine nucleotide bindingpocket is highly conserved among all Hsp90 proteins from bacteria tomammals but is not present in other chaperones.

Hsp90 protein has emerged as an important target in cancer treatment, asmany Hsp90 client proteins themselves were identified as targets forcancer therapies. The exemplary Hsp90 client proteins that areassociated with cancer include HER2 (breast cancer), Raf-1/mutant BRAF(melanoma), Mutant EGFR (non-small cell lung cancer, glioblastoma),c-Kit (GIST), c-Met (gastric, lung, glioblastoma), HIF-1α (renalcancer), Zap70 (chronic lymphocytic leukemia), Bcr-Abl (chronicmyelogenous leukemia), mBcr-Abl (chronic myelogenous leukemia), Flt-3(acute myeloid leukemia), IGF-1R/Akt (myeloma), NMP-ALK (lymphoma), andAkt (small cell lung cancer). Overexpression of mutated Hsp90 client oramplification of its clients, such as HER2, leads to the increaseddependency of tumor cells on Hsp90 chaperone function. Accordingly,Hsp90 provides a compelling target for treating different classes oftumors.

Increased levels of Hsp90 have also been implicated in neurodegenerativedisorders, including Alzheimer's, Parkinson's, and Huntington's disease,and tauopathies. Tauopathies are neurodegenerative diseasescharacterized by tau protein abnormalities, which then result in theaccumulation of hyperphosphorylated and aggregated tau protein. It hasbeen proposed that hyperphosphorylated tau in Alzheimer's disease is apathogenic process caused by aberrant activation of kinases,particularly cdk5 and GSK β3. Studies have shown that Hsp90 stabilizesp35, an activator of cdk5, leading to increased tau phosphorylation. Ithas also been shown that Hsp90 inhibition activates heat shock factor 1(HSF1), which in turn increases the expression of Hsp70. Increasedexpression of Hsp70 promotes tau solubility and binding to microtubules,inhibits Aβ peptide aggregation, and enhances Aβ peptide degradation.

Hsp90 has also emerged as a target for treating viral, fungal, andbacterial infections. For example, an Hsp90 inhibitor (geldanamycin) hasbeen shown to delay the growth of influenza virus in cell culture.

Other viruses that rely on Hsp90 dependent processes include thosebelonging to the families: Herpesviridae (e.g., herpes simplex virus-1,herpes simplex virus-2, herpes herpesvirus-5, Kaposi'ssarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barrvirus), Polyomaviridae (e.g., SV40), Poxviridae (e.g., vaccinia virus),Reoviridae (e.g., rotavirus), Birnaviridae (e.g., infectious bursaldisease virus), picornaviridae (e.g., poliovirus, rhinovirus, orcoxsackievirus), flaviviridae (e.g., hepatitis C virus or dengue virus),arenaviridae (e.g., lymphocytic choriomeningitis virus), Hepeviridae(e.g., Hepatitis E virus), Rhabdoviridae (e.g., vesicular stomatitisvirus), Paramoxyviridae (e.g., human parainfluenza virus 2, humanparainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus),Bunyaviridae (e.g., La Crosse virus), Orthomoxyviridae (e.g., influenzaA virus), Filoviridae (e.g., Ebola virus), Retroviridae (e.g., HTLV1 orHIV1), and Hepadnaviridae (e.g., hepatitis B virus). Hsp90 inhibitorshave also been used in vivo for the treatment of fungal infectiousdiseases, e.g., treatment of Candida albicans, Aspergillus fumigates, orPneumocystis jiroveci. Moreover, Hsp90 inhibitors are also useful in thetreatment of bacterial infections, e.g., mycobacteria, anthrax, orbacterial pneumonia.

In view of the above, inhibitors of Hsp90 represent beneficialtherapeutics for the treatment of disorders, e.g., cancer,neurodegenerative diseases, and infectious diseases.

SUMMARY OF THE INVENTION

In one aspect, the invention features a compound according to formula(I):

or a pharmaceutically acceptable salt thereof,where

-   -   Z¹ is —OR⁷, —N(R¹⁰)R⁷, —SR⁷, or —C(R¹⁰)(R¹¹)R⁷;    -   Z² is —N═ or —C(R³)═;    -   each R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl (e.g., C₁₋₃ acyl);    -   R³ is H, halogen, cyano, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₃ alkoxy, or optionally substituted        amino, and R⁴ is halogen, cyano, optionally substituted C₁₋₆        alkyl, optionally substituted C₁₋₃ alkoxy, optionally        substituted amino, optionally substituted C₁₋₆ thioalkoxy, or        optionally substituted C₆₋₁₀ aryl, or R³ and R⁴, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising        from one to three heteroatoms selected from the group consisting        of nitrogen, oxygen, and sulfur, where the nitrogen is        optionally substituted with R⁹;    -   each R⁵ and R⁶ is, independently, H, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five-, six-, or seven-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur;    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl;    -   R¹⁰ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl, and R¹¹ is H, optionally substituted        C₁₋₃ alkyl, or R¹⁰ and R¹¹ combine to form ═O or ═S; and    -   R^(m) is H, halogen, cyano, optionally substituted C₁₋₄ alkyl        (e.g., C₁₋₄ acyl), or optionally substituted C₁₋₃ alkoxy.

In particular embodiments of formula (I), R^(m) is H (e.g., the compoundof formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof).

In certain embodiments of formula (I), when Z² is CR³, each of R¹ and R²is H, R³ is H, R⁴ is methyl or halogen (e.g., chloro), and each of R⁵and R⁶ is halogen (e.g., chloro),

-   -   Z¹ is not methoxy.

In certain embodiments of formula (I), when Z² is CR³, R³ is H, R⁴ ismethyl or halogen (e.g., chloro), each of R⁵ and R⁶ is halogen (e.g.,chloro),

-   -   Z² is not unsubstituted C₁₋₃ alkoxy.

In particular embodiments of formula (I), when Z² is N, R³ is H, R⁴ isoptionally substituted C₁₋₆ thioalkoxy, and each of R⁵ and R⁶ is halogen(e.g., chloro),

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In other embodiments of formula (I), when Z² is N, R³ is H, each of R⁵and R⁶ is halogen (e.g., chloro), R⁴ is substituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In some embodiments of formula (I), when Z² is N, R³ is H, R⁴ isoptionally substituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In certain embodiments of formula (I), when Z² is N, R³ is H, R⁴ issubstituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In further embodiments of formula (I), when Z² is N, R³ is H, R⁴ issubstituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not substituted C₁ alkoxy.

In particular embodiments of formula (I), when Z² is N, R³ is H, R⁴ issubstituted C₁₋₆ thioalkoxy,

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        methyl, dialkylaminoethyl, optionally substituted C₁₋₃        alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl, or        optionally substituted C₁₋₃ alkaryl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when Z² is CR³, each of R⁵ and R⁶is chloro, R³ is H, and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is not 2-amino-2oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy.

In yet other embodiments of formula (I), when Z² is CR³, R³ is H, and R⁴is halogen (e.g., chloro),

-   -   Z¹ is not 2-amino-2oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy.

In still other embodiments of formula (I), when Z² is CR³, each of R⁵and R⁶ is chloro, R³ is H, and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        dimethylaminoethyl, optionally substituted C₁₋₃ alkcycloalkyl,        or optionally substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸,        together with the atoms to which each is attached, join to form        an optionally substituted five- or six-membered ring optionally        comprising one or two heteroatoms selected from nitrogen,        oxygen, and sulfur.

In further embodiments of formula (I), when Z² is CR³, each of R⁵ and R⁶is chloro, R³ is H, and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments of formula (I), when Z² is CR³, R³ is H, andR⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)ethyl, difluoromethyl, or        2-(t-butylamino)ethyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheteroaryl.

In some embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not alkyl or unsubstituted C₂ alkheteroaryl.

In particular embodiments of formula (I), when R⁵ is chloro, R⁶ isbromo, Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a groupaccording to formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheterocyclyl.

In other embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not alkyl or C₂ alkheterocyclyl.

In still other embodiments of formula (I), when R⁵ is chloro, R⁶ isbromo, Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a groupaccording to formula (IIa),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In yet other embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z² is CR³, and R³ and R⁴ combine to form a group according to formula(IIa),

-   -   Z is —OR⁷, and R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments of formula (I), when each R⁵ and R⁶ is bromo, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not methyl.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIa),

-   -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheteroaryl, or substituted alkheteroaryl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, R⁷ and R⁸ combine to form —CH₂—CH₂—, Z² is CR³, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, R⁷ and R⁸ combine to form —CH₂—CH₂—, Z² is CR³, and R³ and R⁴combine to form a group according to formula (IIa), R⁹ is H or—C(O)—N(H)-(linear C₁₋₃ alkyl).

In particular embodiments of formula (I), when each R⁵ and R⁶ is halo,Z² is CR³, and R³ and R⁴ combine to form a group according to formula(IIa),

-   -   Z is —OR⁷, R⁷ is not methyl or 2-chloroethyl, and R⁹ is H or        —C(O)—N(H)-(linear C₁₋₃ alkyl). In some embodiments of formula        (I), when R⁵ is methoxy, R⁶ is methyl, Z¹ is —OR⁷, Z² is CR³,        and R³ and R⁴ combine to form a group according to formula        (IIa),    -   R⁷ is not methyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is ethyl,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIa),

-   -   R⁷ is not methyl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIb) or (IIc),

-   -   R⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIb) or (IIc),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z²is CR³, and R³ and R⁴ combine to form a group according to formula (IIb)or (IIc),

-   -   Z¹ is —OR⁷, and R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments of formula (I), when R⁷ is methyl, R⁵ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIIa),

-   -   R⁶ is not bromo.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIIa),

-   -   R⁷ is not isopropyl, 3,3,3-trifluoropropyl, or        2-(N,N-dimethylamino)ethyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIIa),

-   -   R⁸ is not H.

In some embodiments of formula (I), when Z² is CR³, and R³ and R⁴combine to form a group according to formula (IIIa),

-   -   each R⁵ and R⁶ is chloro, and    -   R⁷ is methyl and R⁸ is H, or R⁷ and R⁸, together with the atoms        to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when R⁵ is chloro, R⁶ is methoxy,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (Nib):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is methoxy,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (Nib),

-   -   each R¹ and R² is H.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVa):

-   -   R⁷ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVa),

-   -   R⁷ is not substituted alkyl, heterocyclyl, alkheterocyclyl, or        alkaryl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVb):

-   -   R⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVb),

-   -   R⁷ is not substituted alkyl or alkaryl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVc):

-   -   R⁷ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVc),

-   -   R⁷ is not substituted alkyl.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVd):

-   -   R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVd),

-   -   R⁷ is not substituted alkyl or alkheterocyclyl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVe) or (IVf):

-   -   R⁷ is not benzyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVe) or (IVf),

-   -   R⁷ is not alkaryl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVg), (IVh), (IVi), (IVj), or (IVk):

-   -   R⁷ is not methyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVg), (IVh), (IVi), (IVj), or (IVk),

-   -   R⁷ is not alkyl.

In some embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVg), (IVh), (IVi), (IVj), or (IVk),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In particular embodiments of formula (I), when R⁵ is chloro, R⁶ isbromo, Z¹ is —OR⁷, and Z² is CR³,

-   -   R³ and R⁴ do not combine to form a group according to formula        (IVg), (IVh), (IVi), (IVj), or (IVk).

In particular embodiments of formula (I), when R⁶ is methyl,

-   -   each R¹ and R² is H.

In certain embodiments of formula (I), when R³ is H, and each R⁵ and R⁶is chloro,

-   -   R⁷ is not methyl.

In particular embodiments, the compound is according to formula (Ia):

or a pharmaceutically acceptable salt thereof,where

-   -   Z¹ is —OR⁷, —N(R¹⁰)R⁷, —SR⁷, or —C(R¹⁰)(R¹¹)R⁷;    -   each R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   R³ is H, halogen, optionally substituted C₁₋₃ alkyl, or        optionally substituted C₁₋₃ alkoxy, and R⁴ is halogen,        optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃        alkoxy, optionally substituted amino, optionally substituted        C₁₋₆ thioalkyl, or optionally substituted C₆₋₁₀ aryl, or R³ and        R⁴, together with the atoms to which each is attached, join to        form an optionally substituted five-, six-, or seven-membered        ring optionally comprising from one to three heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur, where the nitrogen is optionally substituted with R⁹;    -   each R⁵ and R⁶ is, independently, H, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five-, six-, or seven-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur;    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl;    -   R¹⁰ is H, optionally substituted C₁₋₃ alkyl (e.g., optionally        substituted C₁₋₃ acyl), optionally substituted C₃₋₈ cycloalkyl,        optionally substituted C₆₋₁₀ aryl, optionally substituted C₂₋₉        heteroaryl, optionally substituted C₂₋₉ heterocyclyl, optionally        substituted C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃        alkheterocyclyl, or optionally substituted C₁₋₃ alkaryl, and R¹¹        is H, optionally substituted C₁₋₃ alkyl, or R¹⁰ and R¹¹ combine        to form ═O or ═S.

In other embodiments, when each of R¹ and R² is H, R³ is H, R⁴ is methylor chloro, and each of R⁵ and R⁶ is chloro,

-   -   Z¹ is not methoxy.

In yet other embodiments, when R³ is H, and R⁴ is halogen (e.g.,chloro),

-   -   Z¹ is not 2-amino-2oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy.

In still other embodiments, when each of R⁵ and R⁶ is chloro, R³ is H,and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        dimethylaminoethyl, optionally substituted C₁₋₃ alkcycloalkyl,        or optionally substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸,        together with the atoms to which each is attached, join to form        an optionally substituted five- or six-membered ring optionally        comprising one or two heteroatoms selected from nitrogen,        oxygen, and sulfur.

In further embodiments, when each of R⁵ and R⁶ is chloro, R³ is H, andR⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments, when R³ is H, and R⁴ is halogen (e.g.,chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)ethyl, difluoromethyl, or        2-(t-butylamino)ethyl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheteroaryl.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not alkyl or unsubstituted C₂ alkheteroaryl.

In particular embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheterocyclyl.

In other embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not alkyl or C₂ alkheterocyclyl.

In still other embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In yet other embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   Z is —OR⁷, and R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments, when each R⁵ and R⁶ is bromo, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheteroaryl, or substituted alkheteroaryl.

In other embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, R⁷and R⁸ combine to form —CH₂—CH₂—, and R³ and R⁴ combine to form a groupaccording to formula (IIa),

-   -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl.

In other embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, R⁷ andR⁸ combine to form —CH₂—CH₂—, and R³ and R⁴ combine to form a groupaccording to formula (IIa),

-   -   R⁹ is H or —C(O)—N(H)-(linear C₁₋₃ alkyl).

In particular embodiments, when each R⁵ and R⁶ is halo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   Z is —OR⁷, R⁷ is not methyl or 2-chloroethyl, and R⁹ is H or        —C(O)—N(H)-(linear C₁₋₃ alkyl).

In some embodiments, when R⁵ is methoxy, R⁶ is methyl, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl.

In certain embodiments, when R⁵ is chloro, R⁶ is ethyl, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl.

In some embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIb) or (IIc),

-   -   R⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIb) or (IIc),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In certain embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIb) or (IIc),

-   -   Z¹ is —OR⁷, and R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments, when R⁷ is methyl, R⁵ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IIIa),

-   -   R⁶ is not bromo.

In particular embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IIIa),

-   -   R⁷ is not isopropyl, 3,3,3-trifluoropropyl, or        2-(N,N-dimethylamino)ethyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IIIa),

-   -   R⁸ is not H.

In some embodiments, when R³ and R⁴ combine to form a group according toformula (IIIa),

-   -   each R⁵ and R⁶ is chloro, and    -   R⁷ is methyl and R⁸ is H, or R⁷ and R⁸, together with the atoms        to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments, when R⁵ is chloro, R⁶ is methoxy, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IIIb):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl.

In certain embodiments, when R⁵ is chloro, R⁶ is methoxy, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IIIb),

-   -   each R¹ and R² is H.

In some embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVa):

R⁷ is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolydin-3-yl,1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or3-(N,N-diethylamino)propyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IVa),

-   -   R⁷ is not substituted alkyl, heterocyclyl, alkheterocyclyl, or        alkaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVb):

-   -   R⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IVb),

-   -   R⁷ is not substituted alkyl or alkaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVc):

-   -   R⁷ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl.

In other embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVc),

-   -   R⁷ is not substituted alkyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷,and R³ and R⁴ combine to form a group according to formula (IVd):

-   -   R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IVd),

-   -   R⁷ is not substituted alkyl or alkheterocyclyl.

In some embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVe) or (IVf):

-   -   R⁷ is not benzyl.

In other embodiments, when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVe) or (IVf),

-   -   R⁷ is not alkaryl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IVg), (IVh),(IVi), (IVj), or (IVk):

-   -   R⁷ is not methyl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, andR³ and R⁴ combine to form a group according to formula (IVg), (IVh),(IVi), (IVj), or (IVk),

-   -   R⁷ is not alkyl.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³and R⁴ combine to form a group according to formula (IVg), (IVh), (IVi),(IVj), or (IVk),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In particular embodiments, when R⁵ is chloro, R⁶ is bromo, and Z¹ is—OR⁷,

-   -   R³ and R⁴ do not combine to form a group according to formula        (IVg), (IVh), (IVi), (IVj), or (IVk).

In particular embodiments, when R⁶ is methyl,

-   -   each R¹ and R² is H.

In certain embodiments, when R³ is H, and each R⁵ and R⁶ is chloro,

-   -   R⁷ is not methyl.

In certain embodiments, when R³ and R⁴, together with the atoms to whicheach is attached, join to form a substituted five-membered ringcomprising one nitrogen, the five-membered ring is not substituted withoxo. In particular embodiments, when R³ and R⁴, together with the atomsto which each is attached, join to form a substituted five-membered ringcomprising one sulfur, the five-membered ring is not substituted withhydroxy or C₁₋₃ alkoxy. In further embodiments, when R³ and R⁴, togetherwith the atoms to which each is attached, join to form an optionallysubstituted five-membered ring comprising one sulfur, R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five- or six-membered ring optionally comprisingone or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments, R⁷ and R⁸, together with the atoms to whicheach is attached, join to form an optionally substituted five- orsix-membered ring optionally comprising one or two heteroatoms selectedfrom nitrogen, oxygen, and sulfur. In other embodiments, R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five- or six-membered saturated ring optionallycomprising one or two heteroatoms selected from nitrogen, oxygen, andsulfur. In yet other embodiments, R⁷ and R⁸, together with the atoms towhich each is attached, join to form an optionally substituted five- ofsix-membered ring optionally comprising one or two heteroatoms selectedfrom nitrogen and oxygen. In certain embodiments, R⁷ and R⁸, togetherwith the atoms to which each is attached, join to form an optionallysubstituted five-membered ring.

In some embodiments, a compound is according to formula (Ib):

or a pharmaceutically acceptable salt thereof,

-   -   where    -   each of R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   R³ is H, halogen, optionally substituted C₁₋₃ alkyl, or        optionally substituted C₁₋₃ alkoxy, and R⁴ is halogen,        optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃        alkoxy, optionally substituted amino, optionally substituted        C₁₋₆ thioalkoxy, or optionally substituted C₆₋₁₀ aryl, or R³ and        R⁴, together with the atoms to which each is attached, join to        form an optionally substituted five- or six-membered ring        optionally comprising one nitrogen, one sulfur, or one oxygen,        where the nitrogen is optionally substituted with R⁹;    -   each of R⁵ and R⁶ is, independently, optionally substituted C₁₋₃        alkyl (e.g., optionally substituted C₁₋₃ acyl), optionally        substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five- or six-membered ring; and    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl.

In other embodiments, when each of R¹ and R² is H, R³ is H, R⁴ is methylor chloro, and each of R⁵ and R⁶ is chloro,

-   -   R⁷ is not methyl.

In yet other embodiments, when R³ is H, and R⁴ is halogen (e.g.,chloro),

-   -   R⁷ is not 2-amino-2oxoethyl, 2-(N,N-diethylamino)ethyl, methyl,        or benzyl.

In still other embodiments, when each of R⁵ and R⁶ is chloro, R³ is H,and R⁴ is halogen (e.g., chloro),

-   -   R⁷ is dimethylaminoethyl, optionally substituted C₁₋₃        alkcycloalkyl, or optionally substituted C₁₋₃ alkheterocyclyl,        or R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In further embodiments, when each of R⁵ and R⁶ is chloro, R³ is H, andR⁴ is halogen (e.g., chloro),

-   -   R⁷ is optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments, when R³ is H, and R⁴ is halogen (e.g.,chloro),

-   -   R⁷ is optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)-ethyl, difluoromethyl, or        2-(t-butylamino)ethyl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheteroaryl.

In other embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not alkyl or C₂ alkheteroaryl.

In particular embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheterocyclyl.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not alkyl or C₂ alkheterocyclyl.

In still other embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ andR⁴ combine to form a group according to formula (IIa),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring comprising one oxygen atom and optionally comprising one        more heteroatom selected from nitrogen, oxygen, and sulfur.

In yet other embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments, when each R⁵ and R⁶ is bromo, and R³ and R⁴ combineto form a group according to formula (IIa),

-   -   R⁷ is not methyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheteroaryl, or substituted alkheteroaryl.

In other embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, R⁷ and R⁸ combineto form —CH₂—CH₂—, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl.

In other embodiments, when each R⁵ and R⁶ is chloro, R⁷ and R⁸ combineto form —CH₂—CH₂—, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁹ is H or —C(O)—N(H)-(linear C₁₋₃ alkyl).

In particular embodiments, when each R⁵ and R⁶ is halo, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   and R⁹ is H or —C(O)—N(H)-(linear C₁₋₃ alkyl).

In some embodiments, when R⁵ is methoxy, R⁶ is methyl, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl.

In certain embodiments, when R⁵ is chloro, R⁶ is ethyl, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁷ is not methyl.

In some embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIb) or (IIc),

-   -   R⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments, when each R⁵ and R⁶ is chloro and R³ and R⁴combine to form a group according to formula (IIb) or (IIc),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring comprising one oxygen atom and optionally comprising one        more heteroatom selected from nitrogen, oxygen, and sulfur.

In certain embodiments, when each R⁵ and R⁶ is chloro and R³ and R⁴combine to form a group according to formula (IIb) or (IIc),

-   -   R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments, when R⁷ is methyl, R⁵ is chloro, and R³ and R⁴combine to form a group according to formula (IIIa),

-   -   R⁶ is not bromo.

In particular embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIIa),

-   -   R⁷ is not isopropyl, 3,3,3-trifluoropropyl, or        2-(N,N-dimethylamino)ethyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IIIa),

-   -   R⁸ is not H.

In some embodiments, when R³ and R⁴ combine to form a group according toformula (IIIa),

-   -   each R⁵ and R⁶ is chloro,    -   R⁷ is methyl, and R⁸ is H, or R⁷ and R⁸, together with the atoms        to which each is attached, join to form an optionally        substituted five- or six-membered ring comprising one oxygen        atom and optionally comprising one more heteroatom selected from        nitrogen, oxygen, and sulfur.

In other embodiments, when R⁵ is chloro, R⁶ is methoxy, and R³ and R⁴combine to form a group according to formula (IIIb):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl.

In certain embodiments, when R⁵ is chloro, R⁶ is methoxy, and R³ and R⁴combine to form a group according to formula (IIIb),

-   -   each R¹ and R² is H.

In some embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVa):

-   -   R⁷ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVa),

-   -   R⁷ is not substituted alkyl, heterocyclyl, alkheterocyclyl, or        alkaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVb):

-   -   R⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVb),

-   -   R⁷ is not substituted alkyl or alkaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVc):

-   -   R⁷ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl.

In other embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVc),

-   -   R⁷ is not substituted alkyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVd):

-   -   R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVd),

-   -   R⁷ is not substituted alkyl or alkheterocyclyl.

In some embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVe) or (IVf):

-   -   R⁷ is not benzyl.

In other embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVe) or (IVf),

-   -   R⁷ is not substituted alkyl or alkaryl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IVg), (IVh), (IVi), (IVj),or (IVk):

-   -   R⁷ is not methyl.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴combine to form a group according to formula (IVg), (IVh), (IVi), (IVj),or (IVk),

-   -   R⁷ and R⁸ together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In particular embodiments, when R⁵ is chloro, R⁶ is bromo,

-   -   R³ and R⁴ do not combine to form a group according to formula        (IVg), (IVh), (IVi), (IVj), or (IVk).

In particular embodiments, when R⁶ is methoxy,

-   -   each R¹ and R² is H.

In certain embodiments, when R³ is H, and each R⁵ and R⁶ is chloro,

-   -   R⁷ is not methyl.

In some embodiments of formula (I), (Ia), or (Ib), R³ is H, halogen,optionally substituted C₁₋₃ alkyl (e.g., optionally substituted C₁₋₃acyl), or optionally substituted C₁₋₃ alkoxy, and R⁴ is halogen,optionally substituted C₁₋₃ alkyl (e.g., optionally substituted C₁₋₃acyl), optionally substituted C₁₋₃ alkoxy, optionally substituted amino,optionally substituted C₁₋₆ thioalkyl, or optionally substituted C₆₋₁₀aryl, or R³ and R⁴, together with the atoms to which each is attached,join to form an optionally substituted five- or six-membered ringoptionally comprising one nitrogen, one oxygen, or one sulfur, where thenitrogen is optionally substituted with R⁹.

In further embodiments of formula (I), (Ia), or (Ib), R⁷ is optionallysubstituted C₁₋₃ alkyl, optionally substituted C₁₋₃ alkcycloalkyl,optionally substituted C₁₋₃ alkheterocyclyl, or optionally substitutedC₁₋₃ alkaryl, and R⁸ is H; or R⁷ and R⁸, together with the atoms towhich each is attached, join to form an optionally substituted five- orsix-membered ring optionally comprising one or two heteroatoms selectedfrom nitrogen, oxygen, and sulfur.

In particular embodiments, when R³ and R⁴ combine to form a groupaccording formula (IIb) or (IIc), the carbonyl group of formula (IIb) or(IIc) is proximal to C⁶. In other embodiments, when R³ and R⁴ combine toform a group according to formula (IIb) or (IIc), the carbonyl group offormula (IIb) or (IIc) is proximal to C⁵ or C⁶.

In certain embodiments, when R³ and R⁴ combine to form a group accordingto formula (IIIa), the N atom of the group according to formula (IIIa)is proximal to C⁵. In particular embodiments, when R³ and R⁴ combine toform a group according to formula (IIIa), the N atom of the groupaccording to formula (IIIb) is proximal to C⁵ or C⁶.

In some embodiments, when R³ and R⁴ combine to form a group according toformula (IIIb), the N atom of the group according to formula (IIIb) isproximal to C⁶. In other embodiments, when R³ and R⁴ combine to form agroup according to formula (IIIb), the N atom of the group according toformula (IIIb) is proximal to C⁵ or C⁶.

In particular embodiments, when R³ and R⁴ combine to form a groupaccording to any one of formulae (IVa)-(IVk), the S atom of the groupaccording to any one of formulae (IVa)-(IVk) is proximal to C⁶. Inparticular embodiments, when R³ and R⁴ combine to form a group accordingto any one of formulae (IVa)-(IVk), the S atom of the group according toany one of formulae (IVa)-(IVk) is proximal to C⁵ or C⁶.

In some embodiments, when R³ and R⁴, together with the atoms to whicheach is attached, join to form an optionally substituted five-memberedring comprising one sulfur, R⁷ and R⁸, together with the atoms to whicheach is attached, join to form an optionally substituted five- orsix-membered ring. In certain embodiments, when R³ and R⁴, together withthe atoms to which each is attached, join to form an optionallysubstituted five-membered ring comprising one sulfur, R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five-membered ring. In particular embodiments,when R³ and R⁴, together with the atoms to which each is attached, jointo form an optionally substituted five-membered ring comprising onesulfur, R⁷ and R⁸ combine to form a —CH₂CH₂— group.

In other embodiments, R⁷ and R⁸, together with the atoms to which eachis attached, join to form a five- or six-membered ring.

In particular embodiments, R⁷ is optionally substituted C₁₋₃ alkyl. Inother embodiments, R⁷ is unsubstituted C₁₋₃ alkyl, C₁₋₃alkylamino-C₁₋₃-alkyl (e.g., C₁₋₃ haloalkylamino-C₁₋₃-alkyl (e.g., C₁₋₃fluoroalkylamino-C₁₋₃-alkyl)), di-(C₁₋₃ alkyl)amino-C₁₋₃-alkyl (e.g.,R^(Y1)N(R^(Y2))—(C₁₋₃ alkyl)-, where each of R^(Y1) and R^(Y2) is,independently, unsubstituted C₁₋₃ alkyl or C₁₋₃haloalkylamino-C₁₋₃-alkyl, (e.g., C₁₋₃ fluoroalkylamino-C₁₋₃-alkyl), orC₁₋₃ haloalkyl (e.g., C₁₋₃ fluoroalkyl). In particular embodiments, R⁷is unsubstituted C₁₋₃ alkyl, C₁₋₃ alkylamino-C₁₋₃-alkyl (e.g., C₁₋₃haloalkylamino-C₁₋₃-alkyl, e.g., C₁₋₃ fluoroalkylamino-C₁₋₃-alkyl), ordi-(C₁₋₃ alkyl)amino-C₁₋₃-alkyl (e.g., R^(Y1)N(R^(Y2))—(C₁₋₃ alkyl)-,where each of R^(Y1) and R^(Y2) is, independently, unsubstituted C₁₋₃alkyl, or C₁₋₃ haloalkylamino-C₁₋₃-alkyl, e.g., C₁₋₃fluoroalkylamino-C₁₋₃-alkyl).

In still other embodiments, R⁷ is optionally substituted C₁₋₃ alkyl(e.g., R⁷ is methyl), or R⁷ is —(CH₂)_(k)—N(R²⁴)R²⁵, where k is 2 or 3(e.g., k is 2), and where each of R²⁴ and R²⁵ is, independently, H oroptionally substituted C₁₋₃ alkyl (e.g., each of R²⁴ and R²⁵ is,independently, optionally substituted C₁₋₃ alkyl, e.g., each of R²⁴ andR²⁵ is, independently, C₁₋₃ haloalkyl (e.g., C₁₋₃ fluoroalkyl);alternatively each of R²⁴ and R²⁵ is, independently, unsubstituted C₁₋₃alkyl, e.g., methyl).

In other embodiments, when R³ and R⁴, together with the atoms to whicheach is attached, join to form an optionally substituted five-memberedring comprising one nitrogen, an optional substituent on the ring is notoxo. In certain embodiments, when R³ and R⁴, together with the atoms towhich each is attached, join to form an optionally substitutedfive-membered ring comprising one sulfur, an optional substitutent onthe ring is not hydroxyl or C₁₋₃ alkoxy.

In yet other embodiments, each R¹ and R² is H. In particularembodiments, each R³ and R⁴ is, independently, optionally substitutedC₁₋₃ alkyl or optionally substituted C₁₋₃ alkoxy; or R³ and R⁴, togetherwith the atoms to which each is attached, join to form an optionallysubstituted five- or six-membered ring optionally comprising onenitrogen, one sulfur, or one oxygen, where the nitrogen is optionallysubstituted with R⁹. In some embodiments, R³ and R⁴, together with theatoms to which each is attached, join to form an optionally substitutedfive-membered ring. In certain embodiments, R³ and R⁴ combine to form—CH₂CH₂CH₂—. In particular embodiments, R³ and R⁴, together with theatoms to which each is attached, join to form an optionally substitutedfive-membered ring comprising one nitrogen. In some embodiments, R³ andR⁴ combine to form —N(R⁹)—CH═CH— (e.g., R⁹ is H or optionallysubstituted C₁₋₃ alkyl, e.g., C₁₋₃ haloalkyl (e.g., C₁₋₃ fluoroalkyl);alternatively R⁹ is H). In certain embodiments, the N atom is proximalto C⁵ of Formula (I). In particular embodiments, R³ and R⁴, togetherwith the atoms to which each is attached, join to form an optionallysubstituted five-membered ring comprising one sulfur. In yet otherembodiments, R³ and R⁴ combine to form —C(R^(13A))═C(R^(13B))—S—, whereR^(13A) is H, and R^(13B) is H or optionally substituted C₁₋₃ alkyl. Inparticular embodiments, the S atom is proximal to C⁶ of the compound ofthe invention. In some embodiments, R¹³ is optionally substituted C₁₋₃alkyl, e.g., R^(13B) is —C(O)—R^(13C), where R^(13C) is optionallysubstituted C₁₋₃ alkoxy or optionally substituted amino. In otherembodiments, R⁴ is C₁₋₃ alkyl. In specific embodiments, R⁴ is methyl,ethyl, or isopropyl. In certain embodiments, R⁴ is C₁₋₃ alkoxy (e.g., R⁴is methoxy). In other embodiments, R⁴ is optionally substituted C₁₋₆thioalkoxy (e.g., R⁴ is 4-amino-4-oxobutyl). In yet other embodiments,R⁴ is optionally substituted amino (e.g., R⁴ is methylamino). In stillother embodiments, R⁴ is halogen (e.g., R⁴ is chloro). In particularembodiments, R³ is hydrogen or C₁₋₃ alkyl (e.g., R³ is hydrogen, methyl,or ethyl). In further embodiments, R³ and R⁴ combine to form—C(R^(13A))═C(R^(13B))—S— group, where R^(13A) is H, and R^(13B) is H or—C(O)—R^(13C), where R^(13C) is optionally substituted C₁₋₃ alkyl,optionally substituted C₁₋₃ alkoxy, optionally substituted amino, oroptionally substituted C₂₋₉ heterocyclyl.

In some embodiments, R³ and R⁴ combine to form —X¹—X²—X³—, where

-   -   X¹ is —S—, —O—, —(CR¹⁴R¹⁵)—, —C(R¹⁶)═, —N(R⁹)—, —N═, H, or        optionally substituted C₁₋₃ alkyl;    -   X² is absent, —(CR¹⁷R¹⁸)_(n)—, —S—, —O—, —N═, —N(R⁹)—, —C(R¹⁹)═,        ═N—, ═C(R²⁰)—, or ═C(R²¹)—C(R²²)═;    -   X³ is —(CR¹⁴R¹⁵)—, —S—, —O—, —N(R⁹)—, ═N—, ═C(R²³)—, halogen,        optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₆        thioalkoxy, optionally substituted C₁₋₃ alkoxy, or optionally        substituted C₆₋₁₀ aryl;    -   each R¹⁴ and R¹⁵ is, independently, H or optionally substituted        C₁₋₃ alkyl, or R¹⁴ and R¹⁵ combine to form ═O or ═S;    -   each R¹⁷ and R¹⁸ is, independently, H or optionally substituted        C₁₋₃ alkyl, or R¹⁷ and R¹⁸ combine to form ═O or ═S;    -   each R¹⁶, R¹⁹, R²⁰, R²¹, R²², and R²³ is, independently, H, or        optionally substituted C₁₋₃ alkyl; and    -   n is 1 or 2.

In some embodiments, when X² is not absent,

-   -   the chain of atoms —X¹—X²—X³— includes no more than one        heteroatom, the heteroatom being selected from nitrogen, oxygen,        and sulfur.

In particular embodiments, X¹ is —(CR¹⁴R¹⁵)—, —C(R¹⁶)═, —N(R⁹)—, —N═, oroptionally substituted C₁₋₃ alkyl.

In certain embodiments, X¹ is —(CR¹⁴R¹⁵)—. In particular embodiments,each R¹⁴ and R¹⁵ is H. In other embodiments, X¹ is —C(R¹⁶)═. In yetother embodiments, R¹⁶ is H. In still other embodiments, X¹ is —N(R⁹)—.In some embodiments, R⁹ is H or optionally substituted C₁₋₃ alkyl. Incertain embodiments, R⁹ is hydrogen, methyl, or ethyl. In particularembodiments, X¹ is —N═. In other embodiments, X¹ is optionallysubstituted C₁₋₃ alkyl. In yet other embodiments, X² is absent,—(CH₂)_(n)—, —N(R⁹)—, —C(H)═, ═C(R²⁰)—, or ═C(H)—C(H)═. In still otherembodiments, X² is-C(H)═. In further embodiments, X² is-N(R⁹)—. In someembodiments, R⁹ is H. In certain embodiments, R⁹ is optionallysubstituted C₁₋₃ alkyl (e.g., R⁹ is —C(O)—N(H)-Et). In particularembodiments, X² is ═C(R²⁰)—. In other embodiments, R²⁰ is optionallysubstituted C₁₋₃ alkyl. In yet other embodiments, X² is absent. In stillother embodiments, X³ is —CH₂—, —S—, ═C(H)—, —N(R⁹)—, halogen,optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃ alkoxy,optionally substituted C₁₋₆ thioalkoxy, optionally substituted C₆₋₁₀aryl. In certain embodiments, X³ is —CH₂—. In particular embodiments, X³is-S—. In some embodiments, X³ is ═C(H)—. In other embodiments, X³is-N(R⁹)—. In yet other embodiments, X³ is halogen, optionallysubstituted C₁₋₃ alkyl, optionally substituted C₁₋₃ alkoxy, optionallysubstituted C₁₋₆ thioalkoxy, or optionally substituted C₆₋₁₀ aryl.

In certain embodiments, Z¹ and R⁸ combine to form —Z³—Y¹—Y²—, where

-   -   Z³ is —O—, —N(R¹⁰)—, —N═, —S—, or —(CR¹¹R¹²)—;    -   Y¹ is —O—, —N(R¹⁰)—, —S—, —(CR²⁶R²⁷)_(m)—, —C(R²⁰)═, ═C(R²⁰)—,        ═C(R²¹)—C(R²²)═, optionally substituted C₁₋₃ alkyl, optionally        substituted C₁₋₃ alkheterocyclyl, optionally substituted C₁₋₃        alkcycloalkyl, or optionally substituted C₁₋₃ alkaryl; and    -   Y² is —O—, —S—, —N(R¹⁰)—, —(CR²⁶R²⁷)—, ═C(R²⁰)—, ═N—, or H;        where    -   each R²⁰, R²¹, and R²² is, independently, H or optionally        substituted C₁₋₃ alkyl; and    -   each R²⁶ and R²⁷ is, independently, H or optionally substituted        C₁₋₃ alkyl, or R²⁶ and R²⁷ combine to form ═O or ═S;    -   m is 1 or 2; and        where, when Y² is H,    -   the chain of atoms —Z³—Y¹—Y²— comprises no more than two        heteroatoms, the heteroatom selected from nitrogen, oxygen, and        sulfur.

In yet other embodiments, R⁷ and R⁸ form a group —Y¹—Y²—, where:

-   -   Y¹ is —(CR²⁶R²⁷)_(m)—, —C(R²⁰)═, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkheterocyclyl, optionally        substituted C₁₋₃ alkcycloalkyl, or optionally substituted C₁₋₃        alkaryl; and    -   Y² is —(CR²⁶R²⁷)—, ═C(R²⁰)—, or H; where    -   each R²⁶ and R²⁷ is, independently, H or optionally substituted        C₁₋₃ alkyl; and    -   m is 1 or 2.

In particular embodiments, Z³ is oxygen. In some embodiments, Y¹ is—(CR²⁶R²⁷)_(m)—, —C(R²⁰)═, optionally substituted C₁₋₃ alkyl, optionallysubstituted C₁₋₃ alkheterocyclyl, optionally substituted C₁₋₃alkcycloalkyl, or optionally substituted C₁₋₃ alkaryl. In furtherembodiments, Y¹ is —(CR²⁶R²⁷)_(m)— or optionally substituted C₁₋₃ alkyl.In other embodiments, Y¹ is —(CR²⁶R²⁷)_(m)—. In other embodiments, Y¹ isoptionally substituted C₁₋₃ alkyl (e.g., Y¹ is methyl). In yet otherembodiments, Y¹ is —(CH₂)_(k)—N(R²⁴)R²⁵, where k is 2 or 3, and whereeach R²⁴ and R²⁵ is, independently, H or optionally substituted C₁₋₃alkyl. In still other embodiments, k is 2. In further embodiments, eachR²⁴ and R²⁵ is, independently, optionally substituted C₁₋₃ alkyl (e.g.,each R²⁴ and R²⁵ is methyl). In certain embodiments, Y² is —(CR²⁶R²⁷)—or H. In other embodiments, Y² is —(CR²⁶R²⁷)—.

In some embodiments of any aspect, each R¹ and R² is H

In certain embodiments of formula (I) or (Ia), a compound of theinvention has a structure according to formula (Va):

or a pharmaceutically acceptable salt thereof, where all substituentsare as defined herein.

In particular embodiments of formula (I), (Ia), or (Ib), a compound ofthe invention has a structure according to formula (Vb):

or a pharmaceutically acceptable salt thereof, where

-   -   X¹ is —S—, —O—, —(CR¹⁴R¹⁵)—, —C(R¹⁶)═, —N(R⁹)—, —N═, —H, or        optionally substituted C₁₋₃ alkyl;    -   X² is absent, —(CR¹⁷R¹⁸)_(n)—, —S—, —O—, —N═, —N(R⁹)—, —C(R¹⁹)═,        ═N—, ═C(R²⁰)—, or ═C(R²¹)—C(R²²)═;    -   X³ is —(CR¹⁴R¹⁵)—, —S—, —O—, —N(R⁹)—, ═N—, ═C(R²³)—, halogen,        optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₆        thioalkoxy, optionally substituted C₁₋₃ alkoxy, or optionally        substituted C₆₋₁₀ aryl;    -   Y¹ is —(CR²⁶R²⁷)_(m)—, —C(R²⁰)═, ═C(R²⁰)—, ═C(R²¹)—C(R²²)═,        optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃        alkheterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl, or        optionally substituted C₁₋₃ alkaryl;    -   Y² is —O—, —S—, —N(R¹⁰)—, —(CR²⁶R²⁷)—, ═C(R²⁰)—, ═N—, or H;    -   each R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   each R⁵ and R⁶ is, independently, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   each R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁷, R¹⁸, R²⁰, R¹⁹, R²⁰, R²¹, R²², R²³,        R²⁶, and R²⁷ is, independently, H or optionally substituted C₁₋₃        alkyl;    -   n is 1 or 2; and    -   m is 1 or 2.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, and —X¹—X²—X³—forms a group according to formula (IIa):

-   -   Y¹ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)-ethyl, difluoromethyl, or        2-(t-butylamino)ethyl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   Y¹ is not optionally substituted C₁₋₃ alkyl or optionally        substituted C₂ alkheteroaryl.

In particular embodiments, when R⁵ is chloro, R⁶ is bromo, and—X¹—X²—X³— forms a group according to formula (IIa),

-   -   Y¹ is not optionally substituted C₁₋₃ alkyl or optionally        substituted C₂ alkheterocyclyl.

In still other embodiments, when R⁵ is chloro, R⁶ is bromo, and—X¹—X²—X³— forms a group according to formula (IIa),

-   -   Y² is not H.

In yet other embodiments, when R⁵ is chloro, R⁶ is bromo, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   each Y¹ and Y² is —CH₂—.

In some embodiments, when each R⁵ and R⁶ is bromo, and —X¹—X²—X³— formsa group according to formula (IIa),

-   -   Y¹ is not methyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   Y¹ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   Y¹ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheteroaryl, or substituted alkheteroaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³— formsa group according to formula (IIa),

-   -   Y¹ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, each Y¹ and Y² is—CH₂—, and —X¹—X²—X³— forms a group according to formula (IIa),

-   -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl.

In other embodiments, when each R⁵ and R⁶ is chloro, R⁷ and R⁸ combineto form —CH₂—CH₂—, and —X¹—X²—X³— forms a group according to formula(IIa),

-   -   R⁹ is H or —C(O)—N(H)-(linear C₁₋₃ alkyl).

In particular embodiments, when each R⁵ and R⁶ is halo, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   and R⁹ is H or —C(O)—N(H)-(linear C₁₋₃ alkyl).

In some embodiments, when R⁵ is methoxy, R⁶ is methyl, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   Y¹ is not methyl.

In certain embodiments, when R⁵ is chloro, R⁶ is ethyl, and —X¹—X²—X³—forms a group according to formula (IIa),

-   -   Y¹ is not methyl.

In some embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³— formsa group according to formula (IIb) or (IIc),

-   -   Y¹ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments, when each R⁵ and R⁶ is chloro and —X¹—X²—X³— formsa group according to formula (IIb) or (IIc),

-   -   Y² is not H.

In certain embodiments, when each R⁵ and R⁶ is chloro and —X¹—X²—X³—forms a group according to formula (IIb) or (IIc),

-   -   each Y¹ and Y² is —CH₂—.

In some embodiments, when R⁷ is methyl, R⁵ is chloro, and —X¹—X²—X³—forms a group according to formula (IIIa),

-   -   R⁶ is not bromo.

In particular embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IIIa),

-   -   R⁷ is not isopropyl, 3,3,3-trifluoropropyl, or        2-(N,N-dimethylamino)ethyl.

In some embodiments, when —X¹—X²—X³— forms a group according to formula(IIIa),

-   -   each R⁵ and R⁶ is chloro, and    -   Y¹ is methyl and Y² is H, or    -   Y¹ is —(CR²⁶R²⁷)_(m)—, —C(R²⁰)═, ═C(R²⁰)—, or ═C(R²¹)—C(R²²)═,        and Y² is —O—, —S—, —N(R¹⁰)—, —(CR²⁶R²⁷)—, ═C(R²⁰)—, or ═N—.

In some embodiments, when —X¹—X²—X³— forms a group according to formula(IIIa),

-   -   each R⁵ and R⁶ is chloro, and    -   Y² is not H.

In other embodiments, when R⁵ is chloro, R⁶ is methoxy, and —X¹—X²—X³—forms a group according to formula (IIIb):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl.

In certain embodiments, when R⁵ is chloro, R⁶ is methoxy, and —X¹—X²—X³—forms a group according to formula (IIIb),

-   -   each R¹ and R² is H.

In some embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³— formsa group according to formula (IVa):

-   -   Y¹ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IVa),

-   -   Y¹ is not heterocyclyl, alkheterocyclyl, or alkaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³— formsa group according to formula (IVb):

-   -   Y¹ is not 2-methoxyethyl or benzyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IVb),

-   -   Y¹ is not substituted alkyl or alkaryl.

In some embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³— formsa group according to formula (IVc):

-   -   Y¹ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl.

In other embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IVc),

-   -   Y¹ is not substituted alkyl.

In particular embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IVd):

-   -   Y¹ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments, when each R⁵ and R⁶ is chloro, and R³ and R⁴combine to form a group according to formula (IVd),

-   -   Y¹ is not substituted alkyl or alkheterocyclyl.

In some embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³— formsa group according to formula (IVe) or (IVf):

-   -   Y¹ is not benzyl.

In other embodiments, when each R⁵ and R⁶ is chloro, and —X¹—X²—X³—forms a group according to formula (IVe) or (IVf),

-   -   Y¹ is not alkaryl or substituted alkyl.

In certain embodiments, when R⁵ is chloro, R⁶ is bromo, and —X¹—X²—X³—forms a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

-   -   Y¹ is not methyl.

In some embodiments, when R⁵ is chloro, R⁶ is bromo, —X¹—X²—X³— forms agroup according to formula (IVg), (IVh), (IVi), (IVj), or (IVk),

-   -   Y² is not H.

In particular embodiments, when R⁵ is chloro, R⁶ is bromo,

-   -   R³ and R⁴ do not combine to form a group according to formula        (IVg), (IVh), (IVi), (IVj), or (IVk).

In particular embodiments, when R⁶ is methoxy,

-   -   each R¹ and R² is H.

In certain embodiments, when X¹ is H, and each R⁵ and R⁶ is chloro,

-   -   Y¹ is not methyl.

In some embodiments, R¹⁰ is H, optionally substituted C₁₋₃ alkyl,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₁₋₃alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl, oroptionally substituted C₁₋₃ alkaryl. In other embodiments, R¹⁰ is H,optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl, oroptionally substituted C₁₋₃ alkaryl.

In particular embodiments, when X¹ is —(CR¹⁴R¹⁵)—, X² is —N(R⁹)—, X³ is—(CR¹⁴R¹⁵)—, and each of R¹⁴ and R¹⁵ is H, R⁹ is H or —C(O)—N(H)-Et, andeach of Y¹ and Y² is —CH₂—. In other embodiments, when X¹ is—(CR¹⁴R¹⁵)—, X² is —N(R⁹)—, and X³ is —(CR¹⁴R¹⁵)—, R⁹ is H or—C(O)—N(H)-Et, and each of Y¹ and Y² is —CH₂—. In some embodiments, whenX¹ is —N(R⁹)—, X² is —C(R¹⁹)═, X³ is ═C(R²³)—, and each of R¹⁷, R¹⁹, andR²³ is H, Y¹ is —(CR²⁶R²⁷)_(m)—, and Y² is —(CR²⁶R²⁷)—. In otherembodiments, when X¹ is —N(R⁹)—, X² is —C(R¹⁹)═, X³ is ═C(R²³)—, andeach of R⁹, R¹⁹, and R²³ is H, each of Y¹ and Y² is —CH₂—. In someembodiments, when X¹ is —N(R⁹)—, X² is —C(R¹⁹)═, X³ is ═C(R²³)—, andeach of R¹⁹ and R²³ is H, Y¹ is —(CR²⁶R²⁷)_(m)—, and Y² is —(CR²⁶R²⁷)—.In certain embodiments, when X¹ is —N(R⁹)—, X² is —C(R¹⁹)═, X³ is═C(R²³)—, Y² is H, and each of R⁵ and R⁶ is —Cl, Y¹ is Me. In particularembodiments, when X¹ is —C(R¹⁶)═, X² is ═C(R²⁰)—, and X³ is —S—, R¹⁶ isH. In some embodiments, when X¹ is —C(R¹⁶)═, X² is ═C(R²⁰)—, and X³ is—S—, Y¹ is —(CR²⁶R²⁷)_(m)—, and Y² is —(CR²⁶R²⁷)—. In certainembodiments, when X¹ is —C(R¹⁶)═, X² is ═C(R²⁰)—, and X³ is —S—, each ofY¹ and Y² is —CH₂—. In some embodiments, when X¹ is —C(R¹⁶)═, X² is═C(R²⁰)—, and X³ is —S—, each of R⁵ and R⁶ is —Cl. In certainembodiments, when X¹ is H, and each of R⁵ and R⁶ is Cl, Y¹ is—(CR²⁶R²⁷)_(m)—, and Y² is —(CR²⁶R²⁷)—. In particular embodiments, whenX¹ is H, and each of R⁵ and R⁶ is hal, Y¹ is —(CR²⁶R²⁷)_(m)—, and Y² is—(CR²⁶R²⁷)— (e.g., each of Y¹ and Y² is —CH₂—). In particularembodiments, when X¹ is H, Y¹ is —(CR²⁶R²⁷)_(m)—, and Y² is —(CR²⁶R²⁷)—(e.g., each of Y¹ and Y² is —CH₂—).

In particular embodiments, X¹ is —(CR¹⁴R¹⁵)—, —C(R¹⁶)═, —N(R⁹)—, oroptionally substituted C₁₋₃ alkyl (e.g., —CH₂—, —C(H)═, —N═, optionallysubstituted C₁₋₃ alkyl, or —N(R⁹)— (e.g., R¹⁷ is H or optionallysubstituted C₁₋₃ alkyl (e.g., R⁹ is H, -Me, or -Et).

In some embodiments, X² is absent, —(CH₂)_(n)—, —N(R⁹)—, —C(H)═,═C(R²⁰)—, or ═C(H)—C(H)═. In certain embodiments, X² is absent, —C(H)═,—N(R⁹)— (e.g., R⁹ is H or optionally substituted C₁₋₃ alkyl (e.g., R⁹ isC₁₋₃ haloalkyl, e.g., C₁₋₃ fluoroalkyl), or R⁹ is —C(O)—N(H)-Et), or═C(R²⁰)—, where R²⁰ is, e.g., optionally substituted C₁₋₃ alkyl.

In certain embodiments, X³ is —CH₂—, —S—, ═C(H)—, or optionallysubstituted C₁₋₃ alkyl.

In some embodiments, each of R⁵ and R⁶ is, independently, halo, oroptionally substituted C₁₋₃ alkyl, e.g., each of R⁵ and R⁶ is halo(e.g., each of R⁵ and R⁶ is —Cl).

In some embodiments, R²⁶ is H. In other embodiments, R²⁷ is H. Incertain embodiments, n is 1. In other embodiments, m is 1. In particularembodiments, Y¹ is optionally substituted C₁₋₃ alkyl. In otherembodiments, Y¹ is unsubstituted C₁₋₃ alkyl, C₁₋₃ alkylamino-C₁₋₃-alkyl(e.g., C₁₋₃ haloalkylamino-C₁₋₃-alkyl, e.g., C₁₋₃fluoroalkylamino-C₁₋₃-alkyl), di-(C₁₋₃ alkyl)amino-C₁₋₃-alkyl (e.g.,R^(Y1)N(R^(Y2))—(C₁₋₃ alkyl)-, where each of R^(Y1) and R^(Y2) is,independently, unsubstituted C₁₋₃ alkyl, or C₁₋₃haloalkylamino-C₁₋₃-alkyl, e.g., C₁₋₃ fluoroalkylamino-C₁₋₃-alkyl), orC₁₋₃ haloalkyl (e.g., C₁₋₃ fluoroalkyl). In particular embodiments, Y¹is unsubstituted C₁₋₃ alkyl, C₁₋₃ alkylamino-C₁₋₃-alkyl (e.g., C₁₋₃haloalkylamino-C₁₋₃-alkyl, e.g., C₁₋₃ fluoroalkylamino-C₁₋₃-alkyl), ordi-(C₁₋₃ alkyl)amino-C₁₋₃-alkyl (e.g., R^(Y1)N(R^(Y2))—(C₁₋₃ alkyl)-,where each of R^(Y1) and R^(Y2) is, independently, unsubstituted C₁₋₃alkyl, or C₁₋₃ haloalkylamino-C₁₋₃-alkyl, e.g., C₁₋₃fluoroalkylamino-C₁₋₃-alkyl).

In certain embodiments, a compound of the invention has the formula asshown in Table 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77or a pharmaceutically acceptable salt thereof.

In particular embodiments, a compound of the invention has the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the invention has the formula:

or a pharmaceutically acceptable salt thereof.

In further embodiments, the compound is not compound 38 or compound 39.

In certain embodiments of any formula described herein, each of R¹ andR² is H, R⁵ is Cl, and R⁶ is F or Cl.

In other embodiments of formula (I), (Ia), or (Ib), R³ is H, halogen,optionally substituted C₁₋₃ alkyl, or optionally substituted C₁₋₃alkoxy, and R⁴ is halogen, optionally substituted C₁₋₃ alkyl, optionallysubstituted C₁₋₃ alkoxy, optionally substituted amino, or optionallysubstituted C₁₋₆ thioalkoxy, or R³ and R⁴, together with the atoms towhich each is attached, join to form an optionally substituted five- orsix-membered ring optionally comprising one nitrogen, one oxygen, or onesulfur, where the nitrogen is optionally substituted with R⁹.

In yet other embodiments of formula (I), (Ia), or (Ib), R³ is H,optionally substituted C₁ alkyl, or optionally substituted C₁₋₃ alkoxy,and R⁴ is halogen, optionally substituted C₁₋₃ alkyl, optionallysubstituted C₁₋₃ alkoxy, optionally substituted amino, or optionallysubstituted C₁₋₆ thioalkoxy, or R³ and R⁴, together with the atoms towhich each is attached, join to form an optionally substituted five- orsix-membered ring optionally comprising one nitrogen, one oxygen, or onesulfur, where the nitrogen is optionally substituted with R⁹.

In still other embodiments of formula (I), (Ia), or (Ib), R³ is H,optionally substituted C₁ alkyl, or optionally substituted C₁₋₃ alkoxy,and R⁴ is halogen, optionally substituted C₁₋₃ alkyl, optionallysubstituted C₁₋₃ alkoxy, optionally substituted amino, or optionallysubstituted C₁₋₆ thioalkoxy, or R³ and R⁴ join to form one of thefollowing groups:

-   -   —N(R⁹)—CH═CH—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and        —C(R^(13A))═C(R^(13B))—S—,    -   where N is proximal to position 5, and R⁹ is H or C₁₋₃ alkyl.

In certain embodiments of formula (I), Z² is N, and R⁴ is halogen,optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃ alkoxy,optionally substituted amino, or optionally substituted C₁₋₆ thioalkoxy.

In particular embodiments of formula (I), Z² is N, and R⁴ is optionallysubstituted C₁₋₃ alkoxy or optionally substituted C₁₋₆ thioalkoxy.

In other embodiments, X¹ is —N(R⁹)—, —(CR¹⁴R¹⁵)—, —C(R¹⁶)═, H, oroptionally substituted C₁ alkyl. In yet other embodiments, X² is absent,—(CR¹⁷R¹⁸)_(n)—, —C(R¹⁹)═, or ═C(R²⁰)—. In still other embodiments, X³is —(CR¹⁴R¹⁵)—, —S—, ═C(R²³)—, halogen, optionally substituted C₁₋₃alkyl, optionally substituted C₁₋₆ thioalkoxy, or optionally substitutedC₁₋₃ alkoxy. In certain embodiments, R⁹ is H or C₁₋₃ alkyl.

In some embodiments, the compound of the invention has a molecularweight of less than about 500 g/mol (e.g., less than about 450 g/mol, orless than about 400 g/mol). In other embodiments, the compound of theinvention exhibits apical to basal (A→B) permeability in MDR1-MDCK assayof greater than about 1×10⁻⁷ cm/sec (e.g., greater than about 5×10⁻⁷cm/sec, greater than about 1×10⁻⁶ cm/sec, or greater than about 3×10⁻⁶cm/sec). In particular embodiments, the compound of the inventionexhibits the (B→A)/(A→B) ratio of less than about 30 (e.g., less thanabout 10, less than about 5, or less than about 3).

In another aspect, the invention features a pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt thereof, and one or more of pharmaceutically acceptable carriers orexcipients. In certain embodiments, the composition is formulated foradministration orally, intradermally, intramuscularly, parenterally,intravenously, intra-arterially, intracranially, subcutaneously,intraorbitally, intraventricularly, intraspinally, intraperitoneally, orintranasally. Preferably, the composition is formulated for oraladministration.

In yet another aspect, the invention features a method of treating adisorder in a mammal (e.g., a human) caused by the action of heat shockprotein 90 (Hsp90). The method involves administering to the mammal aneffective amount of a compound according to formula (I):

or a pharmaceutically acceptable salt thereof,where

-   -   Z¹ is —OR⁷, —N(R¹⁰)R⁷, —SR⁷, or —C(R¹⁰)(R¹¹)R⁷;    -   Z² is —N═ or —C(R³)═;    -   each R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   R³ is H, halogen, cyano, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₃ alkoxy, or optionally substituted        amino, and R⁴ is halogen, cyano, optionally substituted C₁₋₆        alkyl, optionally substituted C₁₋₃ alkoxy, optionally        substituted amino, optionally substituted C₁₋₆ thioalkoxy, or        optionally substituted C₆₋₁₀ aryl, or R³ and R⁴, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        nitrogen, one oxygen, or one sulfur, where the nitrogen is        optionally substituted with R⁹;    -   each R⁵ and R⁶ is, independently, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five- or six-membered ring        optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur;    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl;    -   R¹⁰ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl, and R¹¹ is H, optionally substituted        C₁₋₃ alkyl, or R¹⁰ and R¹¹ combine to form ═O or ═S and    -   R^(m) is H, halogen, optionally substituted C₁₋₄ alkyl, or        optionally substituted C₁₋₃ alkoxy.

In certain embodiments of formula (I), when Z² is CR³,each of R¹ and R²is H, R³ is H, R⁴ is methyl or halogen (e.g., chloro), and each of R⁵and R⁶ is halogen (e.g., chloro),

-   -   Z¹ is not methoxy.

In certain embodiments of formula (I), when Z² is CR³, R³ is H, R⁴ ismethyl or halogen (e.g., chloro), each of R⁵ and R⁶ is halogen (e.g.,chloro),

-   -   Z² is not unsubstituted C₁₋₃ alkoxy.

In particular embodiments of formula (I), when Z² is N, R³ is H, R⁴ isoptionally substituted C₁₋₆ thioalkoxy, and each of R⁵ and R⁶ is halogen(e.g., chloro),

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In other embodiments of formula (I), when Z² is N, R³ is H, each of R⁵and R⁶ is halogen (e.g., chloro), R⁴ is substituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In some embodiments of formula (I), when Z² is N, R³ is H, R⁴ isoptionally substituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In certain embodiments of formula (I), when Z² is N, R³ is H, R⁴ issubstituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not cyanomethoxy or aminomethoxy.

In further embodiments of formula (I), when Z² is N, R³ is H, R⁴ issubstituted C₁₋₆ thioalkoxy,

-   -   Z¹ is not substituted C₁ alkoxy.

In particular embodiments of formula (I), when Z² is N, R³ is H, R⁴ issubstituted C₁₋₆ thioalkoxy,

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        methyl, dialkylaminoethyl, optionally substituted C₁₋₃        alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl, or        optionally substituted C₁₋₃ alkaryl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when Z² is CR³, each of R⁵ and R⁶is chloro, R³ is H, and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is not 2-amino-2oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy.

In yet other embodiments of formula (I), when Z² is CR³, R³ is H, and R⁴is halogen (e.g., chloro),

-   -   Z¹ is not 2-amino-2oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy.

In still other embodiments of formula (I), when Z² is CR³, each of R⁵and R⁶ is chloro, R³ is H, and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        dimethylaminoethyl, optionally substituted C₁₋₃ alkcycloalkyl,        or optionally substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸,        together with the atoms to which each is attached, join to form        an optionally substituted five- or six-membered ring optionally        comprising one or two heteroatoms selected from nitrogen,        oxygen, and sulfur.

In further embodiments of formula (I), when Z² is CR³, each of R⁵ and R⁶is chloro, R³ is H, and R⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In particular embodiments of formula (I), when Z² is CR³, R³ is H, andR⁴ is halogen (e.g., chloro),

-   -   Z¹ is —OR⁷, —N(R⁷)R¹⁰, —SR⁷, or —C(R⁷)(R¹⁰)R¹¹, in which R⁷ is        optionally substituted C₁₋₃ alkcycloalkyl, or optionally        substituted C₁₋₃ alkheterocyclyl, or R⁷ and R⁸, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)ethyl, difluoromethyl, or        2-(t-butylamino)ethyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheteroaryl.

In some embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not alkyl or unsubstituted C₂ alkheteroaryl.

In particular embodiments of formula (I), when R⁵ is chloro, R⁶ isbromo, Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a groupaccording to formula (IIa),

-   -   R⁷ is not substituted alkyl, unsubstituted alkyl, or        unsubstituted C₂ alkheterocyclyl.

In other embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is-OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not alkyl or C₂ alkheterocyclyl.

In still other embodiments of formula (I), when R⁵ is chloro, R⁶ isbromo, Z¹ is-OR⁷, Z² is CR³, and R³ and R⁴ combine to form a groupaccording to formula (IIa),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In yet other embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z² is CR³, and R³ and R⁴ combine to form a group according to formula(IIa),

-   -   Z is —OR⁷, and R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments of formula (I), when each R⁵ and R⁶ is bromo, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not methyl.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIa),

-   -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheteroaryl, or substituted alkheteroaryl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not unsubstituted alkyl, substituted alkyl, unsubstituted        alkheterocyclyl, or substituted alkheterocyclyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, R⁷ and R⁸ combine to form —CH₂—CH₂—, Z² is CR³, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, R⁷ and R⁸ combine to form —CH₂—CH₂—, Z² is CR³, and R³ and R⁴combine to form a group according to formula (IIa),

-   -   R⁹ is H or —C(O)—N(H)-(linear C₁₋₃ alkyl).

In particular embodiments of formula (I), when each R⁵ and R⁶ is halo,Z² is CR³, and R³ and R⁴ combine to form a group according to formula(IIa),

-   -   Z is —OR⁷, R⁷ is not methyl or 2-chloroethyl, and R⁹ is H or        —C(O)—N(H)-(linear C₁₋₃ alkyl).

In some embodiments of formula (I), when R⁵ is methoxy, R⁶ is methyl, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIa),

-   -   R⁷ is not methyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is ethyl,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIa),

-   -   R⁷ is not methyl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIb) or (IIc),

R⁷ is not methyl or 2-(N,N-diethylamino)ethyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIb) or (IIc),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z²is CR³, and R³ and R⁴ combine to form a group according to formula (IIb)or (IIc),

-   -   Z¹ is —OR⁷, and R⁷ and R⁸ combine to form —CH₂—CH₂—.

In some embodiments of formula (I), when R⁷ is methyl, R⁵ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIIa),

-   -   R⁶ is not bromo.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IIIa),

-   -   R⁷ is not isopropyl, 3,3,3-trifluoropropyl, or        2-(N,N-dimethylamino)ethyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IIIa),

-   -   R⁸ is not H.

In some embodiments of formula (I), when Z² is CR³, and R³ and R⁴combine to form a group according to formula (IIIa),

-   -   each R⁵ and R⁶ is chloro, and    -   R⁷ is methyl and R⁸ is H, or R⁷ and R⁸, together with the atoms        to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally comprising one        or two heteroatoms selected from nitrogen, oxygen, and sulfur.

In other embodiments of formula (I), when R⁵ is chloro, R⁶ is methoxy,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (Nib):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is methoxy,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (Nib),

-   -   each R¹ and R² is H.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVa):

-   -   R⁷ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVa),

-   -   R⁷ is not substituted alkyl, heterocyclyl, alkheterocyclyl, or        alkaryl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVb):

R⁷ is not 2-methoxyethyl or benzyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVb),

-   -   R⁷ is not substituted alkyl or alkaryl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVc):

R⁷ is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVc),

-   -   R⁷ is not substituted alkyl.

In particular embodiments of formula (I), when each R⁵ and R⁶ is chloro,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVd):

R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl.

In certain embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVd),

-   -   R⁷ is not substituted alkyl or alkheterocyclyl.

In some embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹ is—OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVe) or (IVf):

R⁷ is not benzyl.

In other embodiments of formula (I), when each R⁵ and R⁶ is chloro, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVe) or (IVf),

-   -   R⁷ is not alkaryl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVg), (IVh), (IVi), (IVj), or (IVk):

-   -   R⁷ is not methyl.

In certain embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo,Z¹ is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group accordingto formula (IVg), (IVh), (IVi), (IVj), or (IVk),

-   -   R⁷ is not alkyl.

In some embodiments of formula (I), when R⁵ is chloro, R⁶ is bromo, Z¹is —OR⁷, Z² is CR³, and R³ and R⁴ combine to form a group according toformula (IVg), (IVh), (IVi), (IVj), or (IVk),

-   -   R⁷ and R⁸, together with the atoms to which each is attached,        join to form an optionally substituted five- or six-membered        ring optionally comprising one or two heteroatoms selected from        nitrogen, oxygen, and sulfur.

In particular embodiments of formula (I), when R⁵ is chloro, R⁶ isbromo, Z¹ is —OR⁷, and Z² is CR³,

-   -   R³ and R⁴ do not combine to form a group according to formula        (IVg), (IVh), (IVi), (IVj), or (IVk).

In particular embodiments of formula (I), when R⁶ is methyl, each R¹ andR² is H.

In certain embodiments of formula (I), when R³ is H, and each R⁵ and R⁶is chloro,

-   -   R⁷ is not methyl.

In particular embodiments of formula (I), R^(m) is H (e.g., the compoundof formula (I) has the following structure:

-   -   Z¹ (I), or a pharmaceutically acceptable salt thereof.

In certain embodiments of formula (I), In some embodiments of themethods of the invention, the substituents are defined as describedherein.

In particular embodiments of the methods of the invention, the methodinvolves administering to the mammal an effective amount of a compoundaccording to formula (I). In certain embodiments of the methods of theinvention, the method involves administering to the mammal an effectiveamount of a compound according to formula (Ib). In other embodiments,the method involves administering to the mammal an effective amount of acompound according to formula (Va). In certain embodiments, the methodinvolves administering to the mammal an effective amount of a compoundaccording to formula (Vb). In particular embodiments, the compound maybe selected from Table 2, (e.g., any one of compounds 2, 5-16, 18-27,29, 33-36, 40-48, and 58-77, or a or a pharmaceutically acceptable saltthereof). In further embodiments, the method involves administering tothe mammal an effective amount of compound 38 or 39 or apharmaceutically acceptable salt thereof.

In certain embodiments of the methods of the invention, the methodinvolves treating a mammal having a neurodegenerative disorder byadministering to the mammal the compound of formula (I) (e.g., formula(Ia), (Ib), (Va), or (Vb)).

In some embodiments, the disorder is a neurodegenerative disorder (e.g.,a tauopathy). The neurodegenerative disorder may be Alzheimer's disease,Huntington's disease, progressive supranuclear palsy, Parkinson'ssyndrome, Pick's disease, corticobasal degeneration, chronic traumaticencephalopathy, traumatic brain injury, or frontotemporal dementia.Preferably, the neurodegenerative disorder is Alzheimer's disease. Inother embodiments, the disorder is a proliferative disorder (e.g., acancer, e.g., acute myeloid leukemia, gastrointestinal stromal tumor,gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma,non-small cell lung cancer, renal cancer, small cell lung cancer,blast-phase chronic myelogenous leukemia, leukemia, lymphoproliferativedisorder, metastatic melanoma, relapsed multiple myeloma, refractorymultiple myeloma, myeloproliferative disorders, pancreatic cancer, smallintestine cancer, or solid tumor).

In particular embodiments, the disorder is an inflammatory or autoimmunedisease (e.g., rheumatoid arthritis, systemic lupus erythermatosus, orasthma). In certain embodiments, the disorder is a cardiovasculardisease (e.g., atherosclerosis or cardiomyoapthy). In other embodiments,the disorder is an allergy.

In yet another aspect, the invention features a method of treating aninfectious disease in a mammal by administering an effective amount ofthe compound of the invention (e.g., compounds of the aspects describedabove), or a pharmaceutically acceptable salt thereof to the mammal.

In some embodiments, the infectious disease is a viral infection. Incertain embodiments, the viral infection is a virus of Herpesviridaefamily (e.g., herpes simplex virus-1, herpes simplex virus-2, herpesherpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zostervirus, or Epstein-Barr virus), Polyomaviridae family (e.g., SV40),Poxviridae family (e.g., vaccinia virus), Reoviridae family (e.g.,rotavirus), Birnaviridae family (e.g., infectious bursal disease virus),Picornaviridae family (e.g., poliovirus, rhinovirus, or coxsackievirus),Flaviviridae family (e.g., hepatitis C virus or dengue virus),Arenaviridae family (e.g., lymphocytic choriomeningitis virus),Hepeviridae family (e.g., Hepatitis E virus), Rhabdoviridae family(e.g., vesicular stomatitis virus), Paramoxyviridae family (e.g., humanparainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measlesvirus, or Sendai virus), Bunyaviridae family (e.g., La Crosse virus),Orthomoxyviridae family (e.g., influenza A virus), Filoviridae family(e.g., Ebola virus), Retroviridae family (e.g., HTLV1 or HIV1), orHepadnaviridae family (e.g., hepatitis B virus).

In particular embodiments, the infectious disease is a fungal infection(e.g., Candida albicans, Aspergillus fumigates, or Pneumocystisjiroveci).

In other embodiments, the infectious disease is a bacterial infection(e.g., mycobacteria, anthrax, or bacterial pneumonia).

In some embodiments of any aspect of the methods of the invention, thecompound is administered orally, sublingually, buccally, transdermally,intradermally, intramuscularly, parenterally, intravenously,intra-arterially, intracranially, subcutaneously, intraorbitally,intraventricularly, intraspinally, intraperitoneally, intranasally, byinhalation, and topically. Preferably, the compound is administeredorally.

In certain embodiments of any aspect of the methods of the invention,the mammal is human.

In a further aspect, the invention features a method of inhibiting Hsp90by contacting a cell with the compound of the invention, or apharmaceutically acceptable salt thereof. In some embodiments, themethod is carried out in vitro. In other embodiments, the method iscarried out in vivo.

In another aspect, the invention features a kit containing:

-   -   (i) the pharmaceutical composition of the invention; and    -   (ii) instructions for use of the pharmaceutical compositions        of (i) to treat a disorder in a mammal (e.g., a human) caused by        the action of Hsp90.

In yet another aspect, the invention features the compounds of theinvention for use in treating a disorder caused by the action of heatshock protein 90 (Hsp90). In some embodiments of this aspect, thedisorder is any one of the disorders described in the aspect featuringmethods of the invention. In a related aspect, the invention featuresthe compounds of the invention for use in treating an infectiousdisease. In certain embodiments of this aspect, the infectious diseaseis any one of the infectious diseases described in the aspect featuringmethods of the invention.

In still another aspect, the invention features uses of a compound ofthe invention in treating a disorder caused by the action of heat shockprotein 90 (Hsp90). In some embodiments of this aspect, the disorder canbe any one of the disorders described in the aspect featuring methods ofthe invention. In a related aspect, the invention features uses of acompound of the invention in treating an infectious disease. In certainembodiments of this aspect, the infectious disease is any one of theinfectious diseases described in the aspect featuring methods of theinvention.

In a further aspect, the invention features uses of a compound of theinvention in the manufacture of a medicament for treating a disordercaused by the action of heat shock protein 90 (Hsp90). In someembodiments of this aspect, the disorder can be any one of the disordersdescribed in the aspect featuring methods of the invention. In a relatedaspect, the invention features uses of a compound of the invention inthe manufacture of a medicament for treating an infectious disease. Incertain embodiments of this aspect, the infectious disease is any one ofthe infectious diseases described in the aspect featuring methods of theinvention.

Definitions

Chemical Substituents

The term “about,” as used herein, represents a value that is ±10% of therecited value.

The term “acyl” or “alkanoyl,” as used interchangeably herein, representan alkyl group, as defined herein, or hydrogen attached to the parentmolecular group through a carbonyl group, as defined herein, and isexemplified by formyl, acetyl, propionyl, butanoyl, and the like.Exemplary unsubstituted acyl groups include from 2 to 7 carbons. Acylcan be unsubstituted or substituted in the same as defined for alkyl.

The term “alkaryl,” as defined herein, represents a chemical substituentof formula -(alkylene)-(aryl), where each group is as defined herein andmay be substituted or unsubstituted according to each respectivedefinition.

The term “alkheterocyclyl,” as defined herein, represents a chemicalsubstituent of formula -(alkylene)-(heterocyclyl), where each group isas defined herein and may be substituted or unsubstituted according toeach respective definition.

The term “alkoxy,” as used herein, represents a chemical substituent offormula —OR, where R is a C₁₋₆ alkyl group, unless otherwise specified(e.g., R is C₁₋₃ alkyl). Alkoxy may be unsubstituted or substituted withone, two, or three substituents independently selected from the groupconsisting of: (1) alkoxy of one to six carbons; (2) hydroxyl; (3)amino; (4) alkylamino of one to six carbons; (5) dialkylamino, whereeach of alkyl groups is, independently, one to six carbons; (6)cycloalkyl of three to eight carbons; (7) oxo; (8) hal; (9)alkylsulfonyl of one to six carbon atoms; (10) thioalkoxy of one to sixcarbon atoms; (11) aryl; (12) —CO₂R^(A), where R^(A) is selected fromthe group consisting of (a) hydrogen, (b) alkyl, (c) cycloalkyl, (d)alkcycloalkyl, and (e) alkaryl, where the alkylene group is of one tosix carbon atoms; or (13) —C(O)NR^(B)R^(C), where each of R^(B) andR^(C) is, independently, selected from the group consisting of (a)hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkcycloalkyl, and (e) alkaryl,where the alkylene group is of one to six carbon atoms; with the provisothat no more than one substituent (2)-(5) may be attached to a singlecarbon atom of the alkyl group, and none of the substituents (2)-(5) maybe attached to the carbon connected to the oxygen atom of the alkoxygroup. No more than one oxo substituent may be attached to a singlecarbon of the alkoxy group, and no more than two oxo substituents may befound in any of the alkoxy group as defined herein.

The term “alkoxyalkyl,” as used herein, represents an alkyl group thatis substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkylgroups include from 2 to 9 carbons. In some embodiments, the alkyl andthe alkoxy each can be further substituted with 1, 2, 3, 4, or 5substituent groups as defined herein for each respective group.

The terms “alkyl,” as used herein, are inclusive of both straight chainand branched chain saturated groups of from 1 to 6 carbons, unlessotherwise specified (e.g., from 1 to 3 carbons). Alkyl groups areexemplified by methyl, ethyl, n- and iso-propyl, and may be optionallysubstituted with one, two, three, or, in the case of alkyl groups of twocarbons or more, four substituents, unless otherwise specified,independently selected from the group consisting of: (1) alkoxy of oneto six carbons; (2) hydroxyl; (3) amino; (4) alkylamino of one to sixcarbons; (5) dialkylamino, where each of alkyl groups is, independently,one to six carbons; (6) cycloalkyl of three to eight carbons; (7) oxo;(8) hal; (9) alkylsulfonyl of one to six carbon atoms; (10) thioalkoxyof one to six carbon atoms; (11) aryl; (12) —CO₂R^(A), where R^(A) isselected from the group consisting of (a) hydrogen, (b) alkyl, (c)cycloalkyl, (d) alkcycloalkyl, and (e) alkaryl, where the alkylene groupis of one to six carbon atoms; (13) —C(O)NR^(B)R^(C), where each ofR^(B) and R^(C) is, independently, selected from the group consisting of(a) hydrogen, (b) alkyl, (c) cycloalkyl, (d) alkcycloalkyl, and (e)alkaryl, where the alkylene group is of one to six carbon atoms, orR^(B) and R^(C) combine to form C₂₋₉ heterocyclyl; and (14) cyano; withthe proviso that no more than one substituent (2)-(5) may be attached toa single carbon atom of the alkyl group. No more than one oxosubstituent may be attached to a single carbon of the alkyl group, andno more than two oxo substituents may be found in any of the alkyl groupas defined herein.

The term “alkylene” and the prefix “alk-,” as used herein, represent asaturated divalent C₁₋₁₀ hydrocarbon group derived from a straight orbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, and is exemplified by methylene, ethylene, propylene,isopropylene, and the like. The term “C_(x-y) alkylene” and the prefix“C_(x-y) alk-” represent alkylene groups having between x and y carbons.Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary valuesfor y are 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, thealkylene can be further substituted with 1, 2, 3, or 4 substituentgroups as defined herein for the alkyl group.

The term “alkylsulfonyl,” as used herein, represents an alkyl groupattached to the parent molecular group through an —S(O)₂— group.Exemplary unsubstituted alkylsulfonyl groups are of from 1 to 6 carbons.In some embodiments, the alkyl group can be further substituted with 1,2, 3, or 4 substituent groups as defined herein.

The term “amino,” as used herein, represents a chemical substituent offormula —NH₂. Amino group may be singly substituted with, e.g., analkyl, alkanoyl, aryl, aryloyl, cycloalkyl, heterocyclyl, oralkheterocyclyl group (e.g., “alkylamino” having formula —NH-(optionallysubstituted C₁₋₆ alkyl), e.g., —NH-(unsubstituted C₁₋₆ alkyl)), ordoubly substituted with, e.g., alkyl, alkanoyl, aryl, aryloyl,cycloalkyl, heterocyclyl, or alkheterocyclyl group (e.g., “dialkylamino”having formula —NR′R″, where each of R′ and R″ is, independently,optionally substituted C₁₋₆ alkyl, e.g., —NR′R″, where each of R′ and R″is, independently, unsubstituted C₁₋₆ alkyl). Optionally substitutedC₁₋₆ alkyl group may be a C₁₋₆ haloalkyl, e.g., a C₁₋₆ fluoroalkyl.

The term “aminoalkyl,” as used herein, represents an alkyl group that issubstituted with an amino group. Each of the alkyl and amino groups maybe, independently, substituted or unsubstituted as defined herein foreach respective group.

The term “aryl,” as used herein, represents a mono-, bicyclic, ormulticyclic carbocyclic ring system having between three and twelvecarbons and having one or two aromatic rings. Non-limiting examples ofaryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like.An aryl group may be optionally substituted with one, two, three, four,or five substituents independently selected from the group consistingof: (1) alkyl of one to six carbons; (2) alkoxy of one to six carbons;(3) hydroxyl; (4) amino; (5) alkylamino of one to six carbons; (6)dialkylamino, where each of alkyl groups is, independently, one to sixcarbons; (7) cycloalkyl of three to eight carbons; (8) oxo; (9) hal;(10) alkylsulfonyl of one to six carbon atoms; (11) thioalkoxy of one tosix carbon atoms; (12) aryl; (13) alkaryl, where alkylene group is oneto six carbon atoms; (14) —CO₂R^(A), where R^(A) is selected from thegroup consisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d)alkaryl, and (e) hydrogen, where the alkylene group is of one to sixcarbon atoms; and (15) —C(O)NR^(B)R^(C), where each of R^(B) and R^(C)is, independently, selected from the group consisting of (a) alkyl, (b)cycloalkyl, (c) alkcycloalkyl, (d) alkaryl, and (e) hydrogen, where thealkylene group is of one to six carbon atoms.

The term “aryloyl,” as used herein, represents an aryl group attached tothe parent molecular group through an alkyl group.

The term “carbonyl,” as used herein, represents a C(O) group, which canalso be represented as C═O, and results from the combination of atetravalent carbon atom and an oxo substituent.

The term “cyano,” as used herein represents —CN group.

The term “cyanoalkyl,” as used herein represents an alkyl group that issubstituted with cyano. Exemplary unsubstituted cyanoalkyl groupsinclude from 2 to 9 carbons. In some embodiments, the alkyl group can befurther substituted with 1, 2, 3, 4, or 5 substituent groups as definedherein for each respective group.

The term “cycloalkyl,” as used herein represents a monovalent saturatedor unsaturated non-aromatic cyclic hydrocarbon group of from three toeight carbons, unless otherwise specified, and is exemplified bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.2.1]heptyl, and the like. Cycloalkyl groups may be optionallysubstituted with, for example, one, two, three, or four substituents,independently, selected from the group consisting of: (1) alkyl of oneto six carbons; (2) alkoxy of one to six carbons; (3) hydroxyl; (4)amino; (5) alkylamino of one to six carbons; (6) dialkylamino, whereeach of alkyl groups is, independently, one to six carbons; (7)cycloalkyl of three to eight carbons; (8) oxo; (9) halo; (10)alkylsulfonyl of one to six carbon atoms; (11) thioalkoxy of one to sixcarbon atoms; (12) aryl; (13) alkaryl, where alkylene group is one tosix carbon atoms; (14) —CO₂R^(A), where R^(A) is selected from the groupconsisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaryl,and (e) hydrogen, where the alkylene group is of one to six carbonatoms; or (15) —C(O)NR^(B)R^(C), where each of R^(B) and R^(C) is,independently, selected from the group consisting of (a) alkyl, (b)cycloalkyl, (c) alkcycloalkyl, (d) alkaryl, and (e) hydrogen, where thealkylene group is of one to six carbon atoms, or R^(B) and R^(C) combineto form C₂₋₉ heterocyclyl.

The term “five-membered ring,” as used herein, represent a saturated orunsaturated aromatic or non-aromatic group having five atoms in a cyclicarray, where, unless otherwise specified, four atoms are carbons and theremaining atom is selected from the group consisting of carbon,nitrogen, sulfur, and oxygen. A five-membered ring may be fused toanother cyclic group selected from heterocyclyl, heteroaryl, cycloalkyl,and aryl. A five-membered ring may be unsubstituted or substituted with,for example, one, two, three, or four substituents, independentlyselected from the group consisting of: (1) alkoxy of one to six carbons;(2) hydroxyl; (3) amino; (4) alkylamino of one to six carbons; (5)dialkylamino, where each of alkyl groups is, independently, one to sixcarbons; (6) cycloalkyl of three to eight carbons; (7) oxo; (8)alkylsulfonyl of one to six carbon atoms; (9) thioalkoxy of one to sixcarbon atoms; (10) aryl; (11) alkaryl, where alkylene group is one tosix carbon atoms; (12) optionally substituted alkyl of one to sixcarbons (e.g., unsubstituted alkyl, alkoxyalkyl, hydroxyalkyl,haloalkyl, or cyanoalkyl); (13) —CO₂R^(A), where R^(A) is selected fromthe group consisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl,(d) alkaryl, and (e) hydrogen, where the alkylene group is of one to sixcarbon atoms; (14) —C(O)NR^(B)R^(C), where each of R^(B) and R^(C) is,independently, selected from the group consisting of (a) optionallysubstituted alkyl (e.g., unsubstituted alkyl, alkoxyalkyl, hydroxyalkyl,haloalkyl, or cyanoalkyl), (b) cycloalkyl, (c) alkcycloalkyl, (d)alkaryl, (e) heterocyclyl, (f) alkheterocyclyl, (g) alkoxy, and (h)hydrogen, where the alkylene group is of one to six carbon atoms, orR^(B) and R^(C) combine to form C₂₋₉ heterocyclyl; and (15) cyano.

The term “fluoroalkyl,” as used herein, represents an alkyl group, asdefined herein, where one or more hydrogen radicals (e.g., 1, 2, 3, 4,or 5, or more hydrogen radicals) bound to the alkyl group have beenreplaced by a fluorine radical. In some embodiments, fluoroalkyl groupmay be perfluoroalkyl. Prefix “fluoro” indicates that the group inquestion is substituted by one or more (e.g., 1, 2, 3, 4, or 5, or more)fluorine radicals.

The term “haloalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by a halogen group (i.e., F, Cl, Br, or I).A C₁₋₆ haloalkyl may be substituted with one two, three, or in the caseof alkyl groups of two carbons or more, four or five halogens. Haloalkylgroups include perfluoroalkyls. In certain embodiments, haloalkyl isfluoroalkyl. In some embodiments, the C₁₋₆ haloalkyl group may befurther substituted with 1, 2, 3, or 4 substituent groups as describedherein for alkyl groups.

The terms “halogen,” “hal,” or “halo,” as used interchangeably herein,represent a group selected from fluorine (—F), chlorine (—Cl), bromine(—Br), and iodine (—I). Prefix “halo” indicates that the group inquestion is substituted by a halogen group (i.e., F, Cl, Br, or I).

The term “heterocyclyl,” as used herein represents a 5-, 6- or7-membered ring, unless otherwise specified, containing one, two, three,or four heteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur. The 5-membered ring has zero to two doublebonds, and the 6- and 7-membered rings have zero to three double bonds.The term “heterocyclyl” also represents a heterocyclic compound having abridged multicyclic structure in which one or more carbons and/orheteroatoms bridges two non-adjacent members of a monocyclic ring, e.g.,a quinuclidinyl group. The term “heterocyclyl” also includes bicyclic,tricyclic, and tetracyclic groups in which any of the above heterocyclicrings is fused to one, two, or three carbocyclic rings, e.g., an arylring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, acyclopentene ring, or another monocyclic heterocyclic ring, e.g.,indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl,benzothienyl and the like. Examples of fused heterocyclyls includetropanes and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclics includepyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl,morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl,isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl,thiadiazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,dihydrothienyl, dihydroindolyl, tetrahydroquinolyl,tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl,benzofuranyl, benzothienyl and the like. The heterocyclyl group may beoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of: (1) alkyl of one tosix carbons; (2) alkoxy of one to six carbons; (3) hydroxyl; (4) amino;(5) alkylamino of one to six carbons; (6) dialkylamino, where each ofalkyl groups is, independently, one to six carbons; (7) cycloalkyl ofthree to eight carbons; (8) oxo; (9) hal; (10) alkylsulfonyl of one tosix carbon atoms; (11) thioalkoxy of one to six carbon atoms; (12) aryl;(13) alkaryl; (14) —CO₂R^(A), where R^(A) is selected from the groupconsisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaryl,and (e) hydrogen, where the alkylene group is of one to six carbonatoms; or (15) —C(O)NR^(B)R^(C), where each of R^(B) and R^(C) is,independently, selected from the group consisting of (a) alkyl, (b)cycloalkyl, (c) alkcycloalkyl, (d) alkaryl, and (e) hydrogen, where thealkylene group is of one to six carbon atoms, or R^(B) and R^(C) combineto form C₂₋₉ heterocyclyl.

The term “heteroaryl,” as used herein, represents that subset ofheterocyclyls, as defined herein, which are aromatic: i.e., they contain4n+2 pi electrons within the mono- or multicyclic ring system. In someembodiments, the heteroaryl is substituted with, e.g., 1, 2, 3, or 4substituent groups independently selected from the group consisting of:(1) alkyl of one to six carbons; (2) alkoxy of one to six carbons; (3)hydroxyl; (4) amino; (5) alkylamino of one to six carbons; (6)dialkylamino, where each of alkyl groups is, independently, one to sixcarbons; (7) cycloalkyl of three to eight carbons; (8) oxo; (9) hal;(10) alkylsulfonyl of one to six carbon atoms; (11) thioalkoxy of one tosix carbon atoms; (12) aryl; (13) alkaryl; (14) —CO₂R^(A), where R^(A)is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c)alkcycloalkyl, (d) alkaryl, and (e) hydrogen, where the alkylene groupis of one to six carbon atoms; or (15) —C(O)NR^(B)R^(C), where each ofR^(B) and R^(C) is, independently, selected from the group consisting of(a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaryl, and (e)hydrogen, where the alkylene group is of one to six carbon atoms.

The term “hydroxy,” as used herein, represents an —OH group.

The term “hydroxyalkyl,” as used herein, represents an alkyl group, asdefined herein, substituted by one or two hydroxy groups, with theproviso that no more than one hydroxy group may be attached to a singlecarbon atom of the alkyl group and is exemplified by hydroxymethyl,dihydroxypropyl, and the like.

The term “N-protected amino,” as used herein, refers to an amino group,as defined herein, to which is attached an N-protecting group, asdefined herein.

The term “N-protecting group,” as used herein, represents those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Commonly used N-protecting groups are disclosed inGreene, Protective Groups in Organic Synthesis, 3^(rd) Edition (JohnWiley & Sons, New York, 1999), which is incorporated herein byreference. N-protecting groups include acyl, aroyl, or carbamyl groups,e.g., formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries,e.g., protected or unprotected D, L or D, L-amino acids, e.g., alanine,leucine, phenylalanine, and the like; sulfonyl groups, e.g.,benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forminggroups, e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and thelike, arylalkyl groups, e.g., benzyl, triphenylmethyl, benzyloxymethyl,and the like and silyl groups, e.g., trimethylsilyl, and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc),and benzyloxycarbonyl (Cbz).

The term “six-membered ring,” as used herein, represent a saturated orunsaturated aromatic or non-aromatic group having six atoms in a cyclicarray, where, unless otherwise specified, five atoms are carbons and theremaining atom is selected from the group consisting of carbon,nitrogen, sulfur, and oxygen. A six-membered ring may be fused toanother cyclic group selected from heterocyclyl, heteroaryl, cycloalkyl,and aryl. A six-membered ring may be unsubstituted or substituted with,for example, one, two, three, or four substituents, independentlyselected from the group consisting of: (1) alkyl of one to six carbons;(2) alkoxy of one to six carbons; (3) hydroxyl; (4) amino; (5)alkylamino of one to six carbons; (6) dialkylamino, where each of alkylgroups is, independently, one to six carbons; (7) cycloalkyl of six toeight carbons; (8) oxo; (9) alkylsulfonyl of one to six carbon atoms;(10) thioalkoxy of one to six carbon atoms; (11) aryl; (12) alkaryl,where alkylene group is one to six carbon atoms; (13) —CO₂R^(A), whereR^(A) is selected from the group consisting of (a) alkyl, (b)cycloalkyl, (c) alkcycloalkyl, (d) alkaryl, and (e) hydrogen, where thealkylene group is of one to six carbon atoms; (14) —C(O)NR^(B)R^(C),where each of R^(B) and R^(C) is, independently, selected from the groupconsisting of (a) alkyl, (b) cycloalkyl, (c) alkcycloalkyl, (d) alkaryl,and (e) hydrogen, where the alkylene group is of one to six carbonatoms, or R^(B) and R^(C) combine to form C₂₋₉ heterocyclyl; and (15)cyano.

The term “thioalkoxy,” as used herein, represents a chemical substituentof formula —SR, where R is an alkyl group. In some embodiments, thealkyl group can be further substituted with 1, 2, 3, or 4 substituentgroups as described herein for alkyl groups.

The term “thiol,” as used herein, represents a chemical substituent offormula —SH.

When referring to numbered position within the compounds of theinvention, the following numbering system is employed:

For example, the statement “R³ and R⁴ combine to form —N(R⁹)—CH═CH—”indicates that the nitrogen atom of —N(R⁹)—CH═CH— may be proximal toeither C⁵ carbon or C⁶ carbon. The statement “R³ and R⁴ combine to form—N(R⁹)—CH═CH—” in combination with “the nitrogen atom of —N(R⁹)—CH═CH—is proximal to C⁵” indicates the following compound:

Asymmetric or chiral centers may exist in any of the compounds of thepresent invention. The present invention contemplates the variousstereoisomers and mixtures thereof. Individual stereoisomers ofcompounds of the present invention are prepared synthetically fromcommercially available starting materials that contain asymmetric orchiral centers or by preparation of mixtures of enantiomeric compoundsfollowed by resolution well known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of aracemic mixture of enantiomers, designated (+/−), to a chiral auxiliary,separation of the resulting diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns or by chiral HPLC methods. Methods ofchiral separations have been described previously (G. B. Cox (ed.) inPreparative Enantioselective Chromatography, 2005, BlackwellPublishing). Alternatively, chiral compounds can be prepared by anasymmetric synthesis that favors the preparation of one enantiomer overthe other. Alternatively a chiral pool synthesis (starting with anenantiomerically pure building block) can be used where the chiral groupor center is retained in the intermediate or final product. Enantiomersare designated herein by the symbols “R,” or “S,” depending on theconfiguration of substituents around the chiral atom. Alternatively,enantiomers are designated as (+) or (−) depending on whether a solutionof the enantiomer rotates the plane of polarized light clockwise orcounterclockwise, respectively.

Geometric isomers may also exist in the compounds of the presentinvention. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond and designates suchisomers as of the Z or E configuration, where the term “Z” representssubstituents on the same side of the carbon-carbon double bond and theterm “E” represents substituents on opposite sides of the carbon-carbondouble bond. It is also recognized that for structures in whichtautomeric forms are possible, the description of one tautomeric form isequivalent to the description of both, unless otherwise specified.

Each position in the compounds of the invention may include elements intheir natural isotopic abundance. Alternatively, one or more positionsin the compound of the invention may include an element enriched in anaturally occurring or a synthetic isotope. For example, one or morepositions of the compound of the invention including hydrogen may beenriched with, e.g., deuterium or tritium. In some embodiments, one ormore positions of the compound of the invention including carbon may beenriched with, e.g., ¹⁴C or ¹³C. In other embodiments, one or morepositions of the compound of the invention including nitrogen may beenriched with, e.g., ¹⁵N. In certain embodiments, one or more positionsof the compound of the invention including oxygen may be enriched with,e.g., ¹⁸O, ¹⁷O, or ¹⁵O.

In particular embodiments, one or more positions of the compound of theinvention including fluorine may be enriched with, e.g., ¹⁸F. In otherembodiments, one or more positions of the compound of the inventionincluding carbon may be enriched with, e.g., ³²S, ³³S, ³⁴S, ³⁵S, or ³⁶S.In yet other embodiments, one or more positions of the compound of theinvention including chlorine may be enriched with, e.g., ³⁵Cl, ³⁶Cl, or³⁷Cl.

Some Abbreviations Used Herein:

BINAP—2,2′-bis(diphenylphosphino)-1, Y-binaphthyl;

f-Bu—tert-butyl or 1,1-dimethylethyl;

cat—catecholato;

dppb—bis(diphenylphosphino)butane;

dppf—bis(diphenylphosphino)ferrocene;

Et—ethyl;

Me—methyl;

OAc—acetate;

OMs—mesylate or methanesulfunoate;

ONf—nonaflate or nonafluoro-n-butylsulfonate;

OTf—triflate or trifluoromethanesulfonate;

pin—pinacolato;

i-Pr— isopropyl or 1-methylethyl; and

n-Pr—n-propyl;

SIMes—1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene;

SIPr—1,3,-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene; and

THF—tetrahydrofuran.

Other Terms

The term “about” is used herein to mean a value that is ±10% of therecited value.

The terms “effective amount” or “amount effective to” or“therapeutically effective amount” mean an amount of a compound of theinvention sufficient to produce a desired result, for example, one ormore of a decrease in Hsp90 activity (e.g., inhibition of Hsp90), anincrease in expression of Hsp70, a decrease in aggregation of Aβ peptide(e.g., inhibition of aggregation of Aβ peptide), an increase indegradation of Aβ peptide, and a decrease in phosphorylation of tauprotein, and/or a decrease in, or amelioration of symptoms of, aneurodegenerative disease (e.g., Alzheimer's disease) in a subject uponadministration of a composition containing the compound of theinvention. The increases and decreases related to administration aneffective amount of a compound are relative to levels or symptoms, asapplicable, in a subject that has not been administered a compound ofthe invention or relative to the subject prior to administration of acompound of the invention.

The term “element,” as used herein, refers to a substance consisting ofa single type of atoms, that is, each nucleus of each atom of a singleelement contains the same number of protons.

The term “neurodegeneration,” as used herein, refers to the progressiveloss of structure or function of neurons, including death of neurons.The term “neurodegenerative disease” refers to diseases in whichneurodegeneration is, at least in part, a cause, symptom, or phenotype.

The terms “patient” and “subject,” as used interchangeably herein, referto any animal (e.g., a mammal, e.g., a human). A subject to be treatedaccording to the methods described herein may be one who has beendiagnosed with a neurodegenerative disease, e.g., tauopathy (e.g.,Alzheimer's disease), or a proliferative disease as having such acondition or one at risk of developing the condition. Diagnosis may beperformed by any method or technique known in the art. One skilled inthe art will understand that a subject to be treated according to thepresent invention may have been subjected to standard tests or may havebeen identified, without examination, as one at high risk due to thepresence of one or more risk factors, e.g., increased total level of tauprotein or an increased level of phosphorylated tau protein in a sample(e.g., cerebrospinal fluid) from the subject in comparison to the levelsin a sample from a healthy subject.

The term “pharmaceutical composition,” as used herein, represents acomposition containing a compound described herein, formulated with apharmaceutically acceptable excipient, and manufactured or sold with theapproval of a governmental regulatory agency as part of a therapeuticregimen for the treatment of disease in a mammal. Pharmaceuticalcompositions can be formulated, for example, for oral administration inunit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup);for topical administration (e.g., as a cream, gel, lotion, or ointment);for intravenous administration (e.g., as a sterile solution free ofparticulate emboli and in a solvent system suitable for intravenoususe); or in any other formulation described herein.

The term “pharmaceutically acceptable excipient” or “pharmaceuticallyacceptable carrier,” as used interchangeably herein, refers to anyingredient other than the compounds described herein (e.g., a vehiclecapable of suspending or dissolving the active compound) and having theproperties of being nontoxic and non-inflammatory in a patient.Excipients may include, for example: antiadherents, antioxidants,binders, coatings, compression aids, d is integrants, dyes (colors),emollients, emulsifiers, fillers (diluents), film formers or coatings,flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspending or dispersing agents,sweeteners, or waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, croscarmellose,crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine,ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol,methionine, methylcellulose, methyl paraben, microcrystalline cellulose,polyethyleneglycol, polyvinyl pyrrolidone, povidone, pregelatinizedstarch, propyl paraben, retinyl palmitate, shellac, silicon dioxide,sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate,sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc,titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The term “pharmaceutically acceptable prodrugs” as used herein,represents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use.

The term “pharmaceutically acceptable salt,” as use herein, representsthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example,pharmaceutically acceptable salts are described in: Berge et al., J.Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts:Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth),Wiley-VCH, 2008. The salts can be prepared in situ during the finalisolation and purification of the compounds described herein orseparately by reacting the free base group with a suitable organic acid.Representative acid addition salts include acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate,glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide,hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like, aswell as nontoxic ammonium, quaternary ammonium, and amine cations,including, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine, and the like.

The term “pharmaceutically acceptable solvate” as used herein means acompound as described herein wherein molecules of a suitable solvent areincorporated in the crystal lattice. A suitable solvent isphysiologically tolerable at the dosage administered. For example,solvates may be prepared by crystallization, recrystallization, orprecipitation from a solution that includes organic solvents, water, ora mixture thereof. Examples of suitable solvents are ethanol, water (forexample, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP),dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF),N,N′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU),1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile(ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone,benzyl benzoate, and the like. When water is the solvent, the moleculeis referred to as a “hydrate.”

The abbreviation “PSA” and the term “polar surface area” of a molecule,as used interchangeably herein, are defined as the surface sum over allpolar atoms. The units of PSA are Å² (angstrom squared).

The term “prevent,” as used herein, refers to prophylactic treatment ortreatment that prevents one or more symptoms or conditions of a disease,disorder, or conditions described herein. Preventive treatment thatincludes administration of a compound described herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof, can be acute, short-term, or chronic. The dosesadministered may be varied during the course of preventative treatment.

The term “prodrug,” as used herein, represents compounds that arerapidly transformed in vivo to the parent compound of the above formula,for example, by hydrolysis in blood. Prodrugs of the compounds describedherein may be conventional esters. Some common esters that have beenutilized as prodrugs are phenyl esters, aliphatic (C₁-C₈ or C₈-C₂₄)esters, cholesterol esters, acyloxymethyl esters, carbamates, and aminoacid esters. For example, a compound that contains an OH group may beacylated at this position in its prodrug form. A thorough discussion isprovided in Higuchi and Stella, Pro- drugs as Novel Delivery Systems,Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, and Judkins et at, SyntheticCommunications 26(23):4351-4367, 1996, each of which is incorporatedherein by reference. Preferably, prodrugs of the compounds of thepresent invention are suitable for use in contact with the tissues ofhumans and animals with undue toxicity, irritation, allergic response,and the like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use.

The term “proliferative disease,” as used herein, refers to both cancerand non-cancer disease. The proliferative disease is one characterizedby unregulated proliferation of cells of a certain type (e.g.,astrocytes). Preferably, the tumor cells associated with a proliferativedisease (e.g., cancer) respond to the inhibition of Hsp90 by apoptosis.Proliferative diseases to be treated using compounds of the inventionand according to the methods of the invention may include glioma,meningioma, pituitary adenoma, nerve sheath tumor (e.g., schwannoma orneurofibroma). Proliferative diseases within the scope of the presentinvention may be a cancer, e.g., acute myeloid leukemia,gastrointestinal stromal tumor, gastric cancer, lung cancer, lymphoma,melanoma, myeloma, non-small cell lung cancer, renal cancer, small celllung cancer, blast-phase chronic myelogenous leukemia, leukemia,lymphoproliferative disorder, metastatic melanoma, relapsed multiplemyeloma, refractory multiple myeloma, myeloproliferative disorders,pancreatic cancer, small intestine cancer, or solid tumor. Preferably, aproliferative disease to be treated using compounds of the inventionaccording to the methods of the invention may include brain tumors(e.g., malignant brain tumors). For example, the brain tumors that maybe treated with blood-brain-barrier penetrant compounds of the inventioncan be glioma or meningioma, in particular, glioma (e.g., glioblastoma),or a malignant version thereof. The cancers that may be treatedaccording to the present invention may also be a cancer that hasmetastasized to the brain (e.g., lung cancer, breast cancer, melanoma,colon cancer, renal cancer, and thyroid cancer).

As used herein, and as well understood in the art, “treatment” is anapproach for obtaining beneficial or desired results, e.g., clinicalresults. Beneficial or desired results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions;diminishment of extent of disease, disorder, or condition; stabilized(i.e., not worsening) state of disease, disorder, or condition;preventing spread of disease, disorder, or condition; delay or slowingthe progress of the disease, disorder, or condition; amelioration orpalliation of the disease, disorder, or condition; and remission(whether partial or total), whether detectable or undetectable.“Palliating” a disease, disorder, or condition means that the extentand/or undesirable clinical manifestations of the disease, disorder, orcondition are lessened and/or time course of the progression is slowedor lengthened, as compared to the extent or time course in the absenceof treatment.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a 500 MHz ¹H NMR spectrum of compound 20 in CDCl₃.

FIG. 2 shows a 500 MHz ¹H NMR spectrum of compound 34 in CDCl₃.

FIG. 3 shows a 500 MHz ¹H NMR spectrum of compound 36 in CDCl₃.

FIG. 4 shows five graphs providing IC₅₀ data for compounds 20, 36, 37,and 39 and for a known Hsp90 inhibitor, as measured using a fluorescencepolarization assay described in Example 2.

FIG. 5A shows a graph comparing relative association/dissociation ratesto the concentration of compound 20.

FIG. 5B is a photograph of a gel demonstrating increase of theexpression of Hsp70 at higher concentrations of compound 20 in a cellbased functional assay. Further, FIG. 5B shows that expression of Hsp90remains unchanged relative to variation in the concentration of compound20.

FIG. 6A shows a histogram comparing % cell viability in viable cells(VC), cells contacted with compound 20, and cells contacted with acontrol compound (JNK inhibitor).

FIG. 6B shows a graph comparing pTau231 levels in viable cells (VC),cells contacted with compound 20, and cells contacted with a controlcompound (JNK inhibitor).

FIG. 6C shows a graph comparing pTau396 levels in viable cells (VC),cells contacted with compound 20, and cells contacted with a controlcompound (JNK inhibitor).

FIG. 7 shows a graph of the concentration of compound 20 in mouseplasma. The data in this graph excludes the plasma level of compound 20in animal IRN 12.

FIG. 8 shows a graph of the concentration of compound 20 in mouseplasma. The data in this graph includes all mouse plasma data points.

FIG. 9 shows a graph of the concentration of compound 20 in mouse braintissue. The data in this graph excludes the plasma level of compound 20in animal IRN 12.

FIG. 10 shows a graph of the concentration of compound 20 in mouse braintissue. The data in this graph includes all mouse brain tissue datapoints.

DETAILED DESCRIPTION

The invention features novel aminopyrimidines and related compoundshaving Hsp90 inhibitory activity, pharmaceutical compositions containingthem, and their medical use (e.g., treatment of a proliferative disease(e.g., cancer) or a neurodegenerative disease (e.g., a tauopathy)). Inparticular, the compounds of the invention are capable to penetrateblood-brain-barrier. Therefore, medical use of these compoundsencompasses diseases and conditions afflicting mammalian (e.g., human)brain.

Compounds of the Invention

Exemplary compounds of the invention are shown in Table 2.

TABLE 2

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79or a pharmaceutically acceptable salt thereof.

A non-limiting example of a pharmaceutically acceptable salt of acompound of the invention is:

Exemplary methods for synthesizing compounds of the invention aredescribed herein.

Methods of Preparing Compounds of the Invention

The compounds of the invention can be prepared by processes analogous tothose established in the art, for example, by the reaction sequenceshown in Scheme 1. The numbering system used for the general schemesdoes not necessarily correspond to that employed elsewhere in thedescription or in the claims.

As shown in Scheme 1, one strategy to access compounds of the invention(C) is to utilize standard cross-coupling reactions (e.g., Suzukicoupling, Hiyama coupling, Stille coupling, Negishi coupling,Tamao-Kumada coupling, or Murahashi coupling), where a nucleophile A andan electrophile B are coupled in the presence of a metal salt, e.g., apalladium, copper, iron, or nickel salt (e.g., PdCl₂, Pd(OAc)₂, CuBr,Cul, (CuOTf)₂ toluene complex, Fe(OTf)₃, FeCl₃, FeBr₃, NiCl₂, or NiBr₂).Optionally ligands, e.g., a phosphine (e.g., PPh₃, P(2-furyl)₃,P(f-Bu)₃, dppf, dppb, or BINAP), an N-heterocyclic carbene (e.g., SIMesor SIPr), or di-pyridine (e.g., 2,2′-bipyridyl or 1,10-phenanthroline),may be added to promote the reaction. Alternatively, an organometalliccomplex, e.g., Pd(PPh₃)₄ or (dppf)PdCl₂, may be employed directly withor without additional ligands. Additives, e.g., tetrabutylammoniumfluoride, LiCl, KOAc, or AgOTf, may be added to minimize dehalogenationor to facilitate the cross-coupling reaction. One of skill in the artwould be able to determine an appropriate solvent for the reactionthrough standard screening. Non-limiting examples of solvents used incross-coupling reactions are water, ethanol, acetone, tetrahydrofuran,toluene, 1,4-dioxane, and mixtures thereof. For non-limiting examples ofconditions and catalysts that can be used to prepare a compound of theinvention according to formula C using cross-coupling chemistry, seeMiyaura et al., “Cross-Coupling Reactions: A Practical Guide” in Topicsin Current Chemistry, Springer, 2002, and Nicolaou et al., Angew. Chem.Int. Ed., 44:4442-4489, 2005, which are incorporated herein byreference. Alternatively, a compound of formula A may be an electrophileand have a leaving group X instead of M, while compound of formula B maybe a nucleophile and have a metal or metalloid group M instead of X.

A compound of formula A may be prepared according any method known inthe art, e.g., metal-halogen (e.g., lithium-halogen) exchange (with orwithout a subsequent addition of boron-based, silicon-based, tin-based,zinc-based, or magnesium-based agents), preparation of Grignard reagent,Sandmeyer reaction, or cross-coupling with di-metalloid agent (e.g.,Miyaura borylation reaction). Non-limiting examples of preparation of A(Sandmeyer reaction and lithium halogen exchange to prepare E, andMiyaura borylation reaction to prepare G) are shown in Scheme 2.

A compound of formula B may be prepared according to any method known inthe art, e.g., Biginelli reaction followed by oxidation of the resulting2-aminodihydropyrimidine derivative. Alternatively, a synthetic approachoutlines in Scheme 3 can be used to access a compound of formula B.

As shown in Scheme 3, a compound of formula H may undergo condensationwith a compound of formula I to give a compound of formula J. The aminogroup of 2-aminopyrimidine derivative J may then be protected (P=adivalent N-protecting group, two monovalent N-protecting groups, or onemonovalent N-protecting group and one hydrogen) to furnish a compound offormula K. The hydroxyl group in the compound of formula K may then beconverted to a halogen in the compound of formula L according to anymethod known in the art, e.g., using dehydrating-halogenating reagents(e.g., POCl₃, PCl₅, SOCl₂, SO₂Cl₂, and brominating or iodinatingvariants thereof). Alternatively, the hydroxyl group of the compound offormula K may be converted into a pseudohalogen in the compound offormula L using reagents, e.g., Tf₂O, PhNTf₂, PhNNf₂, or P(O)(OR)₂Cl,and, optionally, a base (e.g., Et₃N, (iPr)₂NEt, or pyridine) and/orcatalyst (e.g., 4-dimethylaminopyridine). N-protecting group P may beremoved from the compound L before or after the cross coupling shown inScheme 1 according to methods known in the art (see, e.g., Greene,Protective Groups in Organic Synthesis, 3^(rd) Edition (John Wiley &Sons, New York, 1999)).

In the reactions described above, it may be necessary to protectreactive functional groups (e.g., hydroxy, amino, thio, or carboxygroups) to avoid their unwanted participation in the reactions. Theincorporation of such groups, and the methods required to introduce andremove them are known to those skilled in the art (for example, Greene,supra). The deprotection step may be the final step in the synthesissuch that the removal of protecting groups affords compounds of formula(Ia) as disclosed herein. Starting materials used in any of the schemesabove can be purchased or prepared by methods described in the chemicalliterature, or by adaptations thereof, using methods known by thoseskilled in the art. The order in which the steps are performed can varydepending on the groups introduced and the reagents used, but would beapparent to those skilled in the art.

Compounds of any of formula (I), (Ia), (Ib), (Va), or (Vb), or any ofthe intermediates described in the schemes above, can be furtherderivatized by using one or more standard synthetic methods known tothose skilled in the art. Such methods can involve substitution,oxidation or reduction reactions. These methods can also be used toobtain or modify compounds of formula (I), (Ia), (Ib), (Va), or (Vb), orany preceding intermediates by modifying, introducing or removingappropriate functional groups. Particular substitution approachesinclude alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulphonylation, nitration, formylation,hydrolysis, and coupling procedures. These procedures can be used tointroduce a functional group onto the parent molecule (e.g., thenitration or sulphonylation of aromatic rings) or to couple twomolecules together (for example to couple an amine to a carboxylic acidto afford an amide; or to form a carbon-carbon bond between twoheterocycles). For example, alcohol or phenol groups can be converted toether groups by coupling a phenol with an alcohol in a solvent, e.g.,tetrahydrofuran in the presence of a phosphine (e.g.,triphenylphosphine) and a dehydrating agent (e.g., diethyl-,diisopropyl-, ordimethylazodicarboxylate). Alternatively, ether groupscan be prepared by deprotonation of an alcohol, using a suitable base(e.g., sodium hydride) followed by the addition of an alkylating agent(e.g., an alkyl halide or an alkylsulphonate).

In another example, a primary or secondary amine can be alkylated usinga reductive alkylation process. For example, the amine can be treatedwith an aldehyde and a borohydride (e.g., sodium triacetoxyborohydride,or sodium cyanoborohydride) in a solvent (e.g., a halogenatedhydrocarbon, for example, dichloromethane, or an alcohol, for example,ethanol) and, where necessary, in the presence of an acid (e.g., aceticacid).

In another example, —OH groups may be generated from the correspondingester, acid, acid chloride or aldehyde by reduction with a suitablereducing agent, e.g., a complex metal hydride, e.g., lithium aluminiumhydride in a solvent (e.g., tetrahydrofuran).

In another example, hydroxy groups (including phenolic OH groups) can beconverted into leaving groups, e.g., halogen atoms or sulphonyloxygroups (e.g., alkylsulphonyloxy, e.g., trifluoromethylsulphonyloxy, orarylsuphonyl, e.g., p-toluenesulphonyloxy) using conditions known tothose skilled in the art. For example, an aliphatic alcohol can bereacted with thionyl chloride in a halogenated hydrocarbon (e.g.,dichloromethane) to afford the corresponding alkylchloride. A base(e.g., triethylamine) can also be used in the reaction.

In another example, ester groups can be converted to the correspondingcarboxylic acid by acid- or base-catalysed hydrolysis depending on thenature of the ester group. Acid catalysed hydrolysis can be achieved bytreatment with an organic or inorganic acid (e.g., trifluoroacetic acidin an aqueous solvent, or a mineral acid, e.g., hydrochloric acid in asolvent, e.g., dioxan). Base catalysed hydrolysis can be achieved bytreatment with an alkali metal hydroxide (e.g., lithium hydroxide in anaqueous alcohol, e.g., methanol).

In another example, aromatic halogen substituents in the compounds maybe subjected to halogen-metal exchange by treatment with a base (e.g., alithium base, e.g., n-butyl or t-butyl lithium) optionally at a lowtemperature (e.g., −78° C.) in a solvent (e.g., tetrahydrofuran) and themixture may then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group can be introduced byusing dimethylformamide as the electrophile. Aromatic halogensubstituents can also be subjected to palladium catalysed reactions tointroduce groups, e.g., carboxylic acids, esters, cyano, or aminosubstituents.

In another example, aromatic halogen substituents in the compounds mayparticipate in a range of metal catalysed reactions to introducealternative functional groups, e.g., amines, amides, ethers, thiols,aryl groups, or heteroaryl groups.

Particular oxidation approaches include dehydrogenations andaromatisation, and the addition of oxygen to certain functional groups.For example, aldehyde groups can be prepared by oxidation of thecorresponding alcohol using conditions well known to those skilled inthe art. For example, an alcohol can be treated with an oxidising agent(e.g., the Dess-Martin reagent) in a solvent (e.g., a halogenatedhydrocarbon, for example dichloromethane). Alternative oxidisingconditions can be used, e.g., treatment with oxalyl chloride and anactivating amount of dimethylsulphoxide and subsequent quenching by theaddition of an amine (e.g., triethylamine). Such a reaction can becarried out in an appropriate solvent (e.g., a halogenated hydrocarbon,for example dichloromethane) and under appropriate conditions (e.g.,cooling below room temperature, e.g., to −78° C. followed by warming toroom temperature). In another example, sulphur atoms can be oxidised tothe corresponding sulphoxide or sulphone using an oxidising agent (e.g.,a peroxy acid, e.g., 3-chloroperoxybenzoic acid) in an inert solvent(e.g., a halogenated hydrocarbon, e.g., dichloromethane) at aroundambient temperature.

Particular reduction approaches include the removal of oxygen atoms fromparticular functional groups, saturation (or partial saturation) ofunsaturated compounds including aromatic rings. For example, primaryalcohols can be generated from the corresponding ester or aldehyde byreduction, using a metal hydride (e.g., lithium aluminium hydride orsodium borohydride in a solvent, e.g., methanol). Alternatively, —OHgroups can be generated from the corresponding carboxylic acid byreduction, using a metal hydride (e.g., lithium aluminium hydride in asolvent, e.g., tetrahydrofuran). In another example, a nitro group maybe reduced to an amine by catalytic hydrogenation in the presence of ametal catalyst (e.g., palladium on a solid support, e.g., carbon) in asolvent (e.g., an ether, e.g., tetrahydrofuran, or an alcohol, e.g.,methanol), or by chemical reduction using a metal (e.g., tin or iron) inthe presence of an acid (e.g., hydrochloric acid). In a further examplean amine can be obtained by reduction of a nitrile, e.g., by catalytichydrogenation in the presence of a metal catalyst (e.g., palladium on asolid support, e.g., carbon), or Raney nickel in a solvent (e.g.,tetrahydrofuran) and under suitable conditions (e.g., cooling to belowroom temperature, e.g., to −78° C., or heating, e.g., to reflux).

Pharmaceutical Compositions

The compounds used in the methods described herein are preferablyformulated into pharmaceutical compositions for administration to humansubjects in a biologically compatible form suitable for administrationin vivo. Pharmaceutical compositions typically include a compound asdescribed herein and a pharmaceutically acceptable excipient.

The compounds described herein can also be used in the form of the freebase, in the form of salts, zwitterions, solvates, or as prodrugs, orpharmaceutical compositions thereof. All forms are within the scope ofthe invention. The compounds, salts, zwitterions, solvates, prodrugs, orpharmaceutical compositions thereof, may be administered to a patient ina variety of forms depending on the selected route of administration, aswill be understood by those skilled in the art. The compounds used inthe methods described herein may be administered, for example, by oral,parenteral, buccal, sublingual, nasal, rectal, patch, pump, ortransdermal administration, and the pharmaceutical compositionsformulated accordingly. Parenteral administration includes intravenous,intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal,intrapulmonary, intrathecal, rectal, and topical modes ofadministration. Parenteral administration may be by continuous infusionover a selected period of time.

For human use, a compound of the invention can be administered alone orin admixture with a pharmaceutical carrier selected with regard to theintended route of administration and standard pharmaceutical practice.Pharmaceutical compositions for use in accordance with the presentinvention thus can be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries that facilitate processing of compounds of Formula (I),(Ia), (Ib), (Va), or (Vb) into preparations which can be usedpharmaceutically.

This invention also includes pharmaceutical compositions which cancontain one or more pharmaceutically acceptable carriers. In making thepharmaceutical compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semisolid, or liquid material (e.g., normal saline),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,and soft and hard gelatin capsules. As is known in the art, the type ofdiluent can vary depending upon the intended route of administration.The resulting compositions can include additional agents, e.g.,preservatives.

The excipient or carrier is selected on the basis of the mode and routeof administration. Suitable pharmaceutical carriers, as well aspharmaceutical necessities for use in pharmaceutical formulations, aredescribed in Remington: The Science and Practice of Pharmacy, 21^(st)Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-knownreference text in this field, and in the USP/NF (United StatesPharmacopeia and the National Formulary). Examples of suitableexcipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches,gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water, syrup, and methyl cellulose. The formulations can additionallyinclude: lubricating agents, e.g., talc, magnesium stearate, and mineraloil; wetting agents; emulsifying and suspending agents; preservingagents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents;and flavoring agents. Other exemplary excipients are described inHandbook of Pharmaceutical Excipients, 6^(th) Edition, Rowe et al.,Eds., Pharmaceutical Press (2009).

These pharmaceutical compositions can be manufactured in a conventionalmanner, e.g., by conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping, orlyophilizing processes. Methods well known in the art for makingformulations are found, for example, in Remington: The Science andPractice of Pharmacy, 21^(st) Ed., Gennaro, Ed., Lippencott Williams &Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J.Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Properformulation is dependent upon the route of administration chosen. Theformulation and preparation of such compositions is well-known to thoseskilled in the art of pharmaceutical formulation. In preparing aformulation, the active compound can be milled to provide theappropriate particle size prior to combining with the other ingredients.If the active compound is substantially insoluble, it can be milled to aparticle size of less than 200 mesh. If the active compound issubstantially water soluble, the particle size can be adjusted bymilling to provide a substantially uniform distribution in theformulation, e.g., about 40 mesh.

Dosages

The dosage of the compound used in the methods described herein, orpharmaceutically acceptable salts or prodrugs thereof, or pharmaceuticalcompositions thereof, can vary depending on many factors, e.g., thepharmacodynamic properties of the compound; the mode of administration;the age, health, and weight of the recipient; the nature and extent ofthe symptoms; the frequency of the treatment, and the type of concurrenttreatment, if any; and the clearance rate of the compound in the animalto be treated.

One of skill in the art can determine the appropriate dosage based onthe above factors. The compounds used in the methods described hereinmay be administered initially in a suitable dosage that may be adjustedas required, depending on the clinical response. In general, a suitabledaily dose of a compound of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above.

A compound of the invention may be administered to the patient in asingle dose or in multiple doses. When multiple doses are administered,the doses may be separated from one another by, for example, 1-24 hours,1-7 days, 1-4 weeks, or 1-12 months. The compound may be administeredaccording to a schedule or the compound may be administered without apredetermined schedule. An active compound may be administered, forexample, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day, every2^(nd), 3^(rd), 4^(th), 5^(th), or 6^(th) day, 1, 2, 3, 4, 5, 6, or 7times per week, 1, 2, 3, 4, 5, or 6 times per month, or 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 times per year. It is to be understood that,for any particular subject, specific dosage regimes should be adjustedovertime according to the individual need and the professional judgmentof the person administering or supervising the administration of thecompositions.

While the attending physician ultimately will decide the appropriateamount and dosage regimen, an effective amount of a compound of theinvention may be, for example, a total daily dosage of, e.g., between0.05 mg and 3000 mg of any of the compounds described herein.Alternatively, the dosage amount can be calculated using the body weightof the patient. Such dose ranges may include, for example, between10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200,250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900,950, or 1000 mg of the compound is administered.

In the methods of the invention, the time period during which multipledoses of a compound of the invention are administered to a patient canvary. For example, in some embodiments doses of the compounds of theinvention are administered to a patient over a time period that is 1-7days; 1-12 weeks; or 1-3 months. In other embodiments, the compounds areadministered to the patient over a time period that is, for example,4-11 months or 1-30 years. In other embodiments, the compounds areadministered to a patient at the onset of symptoms. In any of theseembodiments, the amount of compound that is administered may vary duringthe time period of administration. When a compound is administereddaily, administration may occur, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 times per day.

Formulations

A compound identified as capable of treating any of the conditionsdescribed herein, using any of the methods described herein, may beadministered to patients or animals with a pharmaceutically-acceptablediluent, carrier, or excipient, in unit dosage form. The chemicalcompounds for use in such therapies may be produced and isolated by anystandard technique known to those in the field of medicinal chemistry.Conventional pharmaceutical practice may be employed to provide suitableformulations or compositions to administer the identified compound topatients suffering from a disease in which necrosis occurs.Administration may begin before the patient is symptomatic.

Exemplary routes of administration of the compounds (e.g., the compoundshaving Formula (I), (Ia), (Ib), (Va) or (Vb)), or pharmaceuticalcompositions thereof, used in the present invention include oral,sublingual, buccal, transdermal, intradermal, intramuscular, parenteral,intravenous, intra-arterial, intracranial, subcutaneous, intraorbital,intraventricular, intraspinal, intraperitoneal, intranasal, inhalation,and topical administration. The compounds desirably are administeredwith a pharmaceutically acceptable carrier. Pharmaceutical formulationsof the compounds described herein formulated for treatment of thedisorders described herein are also part of the present invention.

Formulations for Oral Administration

The pharmaceutical compositions contemplated by the invention includethose formulated for oral administration (“oral dosage forms”). Oraldosage forms can be, for example, in the form of tablets, capsules, aliquid solution or suspension, a powder, or liquid or solid crystals,which contain the active ingredient(s) in a mixture with non-toxicpharmaceutically acceptable excipients. These excipients may be, forexample, inert diluents or fillers (e.g., sucrose, sorbitol, sugar,mannitol, microcrystalline cellulose, starches including potato starch,calcium carbonate, sodium chloride, lactose, calcium phosphate, calciumsulfate, or sodium phosphate); granulating and disintegrating agents(e.g., cellulose derivatives including microcrystalline cellulose,starches including potato starch, croscarmellose sodium, alginates, oralginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia,alginic acid, sodium alginate, gelatin, starch, pregelatinized starch,microcrystalline cellulose, magnesium aluminum silicate,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethyleneglycol); and lubricating agents, glidants, and antiadhesives (e.g.,magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenatedvegetable oils, or talc). Other pharmaceutically acceptable excipientscan be colorants, flavoring agents, plasticizers, humectants, bufferingagents, and the like.

Formulations for oral administration may also be presented as chewabletablets, as hard gelatin capsules wherein the active ingredient is mixedwith an inert solid diluent (e.g., potato starch, lactose,microcrystalline cellulose, calcium carbonate, calcium phosphate orkaolin), or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil. Powders, granulates, and pellets may be preparedusing the ingredients mentioned above under tablets and capsules in aconventional manner using, e.g., a mixer, a fluid bed apparatus or aspray drying equipment.

Controlled release compositions for oral use may be constructed torelease the active drug by controlling the dissolution and/or thediffusion of the active drug substance. Any of a number of strategiescan be pursued in order to obtain controlled release and the targetedplasma concentration versus time profile. In one example, controlledrelease is obtained by appropriate selection of various formulationparameters and ingredients, including, e.g., various types of controlledrelease compositions and coatings. Examples include single or multipleunit tablet or capsule compositions, oil solutions, suspensions,emulsions, microcapsules, microspheres, nanoparticles, patches, andliposomes. In certain embodiments, compositions include biodegradable,pH, and/or temperature-sensitive polymer coatings.

Dissolution or diffusion controlled release can be achieved byappropriate coating of a tablet, capsule, pellet, or granulateformulation of compounds, or by incorporating the compound into anappropriate matrix. A controlled release coating may include one or moreof the coating substances mentioned above and/or, e.g., shellac,beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerylmonostearate, glyceryl distearate, glycerol palmitostearate,ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetatebutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone,polyethylene, polymethacrylate, methylmethacrylate,2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol,ethylene glycol methacrylate, and/or polyethylene glycols. In acontrolled release matrix formulation, the matrix material may alsoinclude, e.g., hydrated methylcellulose, carnauba wax and stearylalcohol, carbopol 934, silicone, glyceryl tristearate, methylacrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/orhalogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils, e.g., cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Formulations for Buccal Administration

Dosages for buccal or sublingual administration typically are 0.1 to 500mg per single dose as required. In practice, the physician determinesthe actual dosing regimen which is most suitable for an individualpatient, and the dosage varies with the age, weight, and response of theparticular patient. The above dosages are exemplary of the average case,but individual instances exist wherein higher or lower dosages aremerited, and such are within the scope of this invention.

For buccal administration, the compositions may take the form oftablets, lozenges, etc. formulated in a conventional manner. Liquid drugformulations suitable for use with nebulizers and liquid spray devicesand electrohydrodynamic (EHD) aerosol devices will typically include acompound of the invention with a pharmaceutically acceptable carrier.Preferably, the pharmaceutically acceptable carrier is a liquid, e.g.,alcohol, water, polyethylene glycol, or a perfluorocarbon. Optionally,another material may be added to alter the aerosol properties of thesolution or suspension of compounds of the invention. Desirably, thismaterial is liquid, e.g., an alcohol, glycol, polyglycol, or a fattyacid. Other methods of formulating liquid drug solutions or suspensionsuitable for use in aerosol devices are known to those of skill in theart (see, e.g., Biesalski, U.S. Pat. No. 5,112,598 and Biesalski, U.S.Pat. No. 5,556,611, each of which is herein incorporated by reference).

Formulations for Nasal or Inhalation Administration

The compounds may also be formulated for nasal administration.Compositions for nasal administration also may conveniently beformulated as aerosols, drops, gels, and powders. The formulations maybe provided in a single or multidose form. In the case of a dropper orpipette, dosing may be achieved by the patient administering anappropriate, predetermined volume of the solution or suspension. In thecase of a spray, this may be achieved, for example, by means of ametering atomizing spray pump.

The compounds may further be formulated for aerosol administration,particularly to the respiratory tract by inhalation and includingintranasal administration. The compound will generally have a smallparticle size for example on the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant, e.g., a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant, e.g., lecithin. Thedose of drug may be controlled by a metered valve. Alternatively, theactive ingredients may be provided in a form of a dry powder, e.g., apowder mix of the compound in a suitable powder base, e.g., lactose,starch, and starch derivatives, e.g., hydroxypropylmethyl cellulose, andpolyvinylpyrrolidine (PVP). The powder carrier will form a gel in thenasal cavity. The powder composition may be presented in unit dose formfor example in capsules or cartridges of e.g., gelatin or blister packsfrom which the powder may be administered by means of an inhaler.

Aerosol formulations typically include a solution or fine suspension ofthe active substance in a physiologically acceptable aqueous ornon-aqueous solvent and are usually presented in single or multidosequantities in sterile form in a sealed container, which can take theform of a cartridge or refill for use with an atomizing device.Alternatively, the sealed container may be a unitary dispensing device,e.g., a single dose nasal inhaler or an aerosol dispenser fitted with ametering valve which is intended for disposal after use. Where thedosage form comprises an aerosol dispenser, it will contain apropellant, which can be a compressed gas, e.g., compressed air or anorganic propellant, e.g., fluorochlorohydrocarbon. The aerosol dosageforms can also take the form of a pump-atomizer.

Formulations for Parenteral Administration

The compounds described herein for use in the methods of the inventioncan be administered in a pharmaceutically acceptable parenteral (e.g.,intravenous or intramuscular) formulation as described herein. Thepharmaceutical formulation may also be administered parenterally(intravenous, intramuscular, subcutaneous or the like) in dosage formsor formulations containing conventional, non-toxic pharmaceuticallyacceptable carriers and adjuvants. In particular, formulations suitablefor parenteral administration include aqueous and non-aqueous sterileinjection solutions which may contain anti-oxidants, buffers,bacteriostats and solutes which render the formulation isotonic with theblood of the intended recipient; and aqueous and non-aqueous sterilesuspensions which may include suspending agents and thickening agents.For example, to prepare such a composition, the compounds of theinvention may be dissolved or suspended in a parenterally acceptableliquid vehicle. Among acceptable vehicles and solvents that may beemployed are water, water adjusted to a suitable pH by addition of anappropriate amount of hydrochloric acid, sodium hydroxide or a suitablebuffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloridesolution. The aqueous formulation may also contain one or morepreservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate.Additional information regarding parenteral formulations can be found,for example, in the United States Pharmacopeia-National Formulary(USP—NF), herein incorporated by reference.

The parenteral formulation can be any of the five general types ofpreparations identified by the USP-NF as suitable for parenteraladministration:

-   -   (1) “Drug Injection:” a liquid preparation that is a drug        substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or        (Vb)), or a solution thereof;    -   (2) “Drug for Injection:” the drug substance (e.g., a compound        of Formula (I), (Ia), (Ib), (Va) or (Vb)) as a dry solid that        will be combined with the appropriate sterile vehicle for        parenteral administration as a drug injection;    -   (3) “Drug Injectable Emulsion:” a liquid preparation of the drug        substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or        (Vb)) that is dissolved or dispersed in a suitable emulsion        medium;    -   (4) “Drug Injectable Suspension:” a liquid preparation of the        drug substance (e.g., a compound of Formula (I), (Ia), (Ib),        (Va) or (Vb)) suspended in a suitable liquid medium; and    -   (5) “Drug for Injectable Suspension:” the drug substance (e.g.,        a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)) as a dry        solid that will be combined with the appropriate sterile vehicle        for parenteral administration as a drug injectable suspension.

Exemplary formulations for parenteral administration include solutionsof the compound prepared in water suitably mixed with a surfactant,e.g., hydroxypropylcellulose. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, DMSO and mixtures thereof with orwithout alcohol, and in oils. Under ordinary conditions of storage anduse, these preparations may contain a preservative to prevent the growthof microorganisms. Conventional procedures and ingredients for theselection and preparation of suitable formulations are described, forexample, in Remington: The Science and Practice of Pharmacy, 21^(st)Ed., Gennaro, Ed., Lippencott Williams & Wlkins (2005) and in The UnitedStates Pharmacopeia: The National Formulary (USP 36 NF31), published in2013.

Formulations for parenteral administration may, for example, containexcipients, sterile water, or saline, polyalkylene glycols, e.g.,polyethylene glycol, oils of vegetable origin, or hydrogenatednapthalenes. Biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers may be used to control the release of the compounds. Otherpotentially useful parenteral delivery systems for compounds includeethylene-vinyl acetate copolymer particles, osmotic pumps, implantableinfusion systems, and liposomes. Formulations for inhalation may containexcipients, for example, lactose, or may be aqueous solutionscontaining, for example, polyoxyethylene-9-lauryl ether, glycocholateand deoxycholate, or may be oily solutions for administration in theform of nasal drops, or as a gel.

The parenteral formulation can be formulated for prompt release or forsustained/extended release of the compound. Exemplary formulations forparenteral release of the compound include: aqueous solutions, powdersfor reconstitution, cosolvent solutions, oil/water emulsions,suspensions, oil-based solutions, liposomes, microspheres, and polymericgels.

Methods of Treatment

The compounds and compositions described herein can be used in thetreatment of conditions and disorders in which Hsp90 has beenimplicated, e.g., cell proliferative disorders, e.g., cancers,neurodegenerative diseases, e.g., tauopathies (e.g., Alzheimer'sdisease), and infectious diseases.

Cell Proliferative Disorders

Hsp90 has emerged as a key therapeutic target for cancer therapy due tothe involvement of this multichaperone complex in various pathogeniccellular processes. Hsp90 client proteins include those implicated in:acute myeloid leukemia (Flt-3), breast cancer (HER2), chronic lymphoidleukemia (Zap70), chronic myeloid leukemia (Bcr-Abl or mBcr-Abl),gastrointestinal stromal tumor (c-Kit), gastric cancer (c-Met),glioblastoma (mutant EGFR orc-Met), lung cancer (c-Met), lymphoma(NMP-ALK), melanoma (Raf-1/mutant BRAF), myeloma (IGF-1R/Akt), non-smallcell lung cancer (mutant EGFR), renal cancer, (HIF-1α), and small celllung cancer (Akt). The compounds of the invention are particularlyuseful in the treatment of brain tumors due to their blood-brain-barrierpenetrant properties. Brain tumors that may be treated using compoundsof the invention include glioma or meningioma, in particular, glioma(e.g., glioblastoma) or neuroblastoma. The brain tumors (e.g., braincancers) that may be treated using compounds of the invention accordingto the methods of the invention may include primary tumors (those tumorsthat originated in the brain) and metastatic tumors (those tumors thatoriginated in tissues other than brain tissues and spread to the brain).Still other cell proliferative disorders that may be treated by theinhibition of Hsp90 include: blast-phase chronic myelogenous leukemia,leukemia, lymphoproliferative disorder, metastatic melanoma, multiplemyeloma (e.g., relapsed or refractory multiple myeloma),myeloproliferative disorders, pancreatic cancer, small intestine cancer,and solid tumor. Moreover, cancer cells have been shown to be moresensitive to Hsp90 inhibition than non-pathogenic cells. Accordingly,the compounds described herein may be useful treatments for cellproliferative disorders.

Neurodegenerative Diseases

Increased levels of Hsp90 have been implicated in neurodegenerativedisorders. For example, aberrant Hsp90 activity has been shown intauopathies, which are conditions characterized by accumulation ofabnormal Tauproteins (e.g., hyperphosphorylated and aggregated Tau).Accordingly, compounds and compositions described herein can be usefulfor the treatment of neurodegenerative diseases and tauopathies thatinclude Alzheimer's disease (AD), argyrophilic grain disease,amyotrophic lateral sclerosis, corticobasal degeneration, dementiapugislistica, Down's syndrome, familial British dementia, frontal lobedegeneration (dementia lacking distinctive histopathological features),chronic traumatic encephalopathy, traumatic brain injury, frontotemporaldementia (FTD; e.g., fronto-temporal dementia with parkinsonism linkedto chromosome 17 (FTDP-17)), hippocampal tauopathy in cerebral aging,myotonic dystrophy of type I, Niemann-Pick disease of type C,Parkinson's disease (e.g., parkinsonism-dementia complex of Guam,Parkinsonism with dementia of Guadeloupe, or postencephaliticparkinsonism), Pick's disease (PiD), and progressive supranuclear palsy.Accordingly, the compounds described herein may be useful in treating aneurodegenerative disorder, e.g., tauopathy (e.g., Alzheimer's disease).

Infectious Diseases

Hsp90 has emerged as a therapeutic target for treating infectiousdiseases, e.g., viral infections, fungal infections, and bacterialinfections. Many pathogens (e.g., viruses, fungi, and bacteria) rely onHsp90-dependent processes (see, e.g., Geller et al., Biochim. Biophys.Acta-Mol. Cell Res., 1823:698-706, 2012; the disclosure of which isincorporate herein in its entirety). Thus, inhibition of Hsp90 providesa therapeutic benefit to a patient afflicted with an infection thatrelies on the activity of Hsp90. For example, an Hsp90 inhibitor(geldanamycin) was shown to delay the growth of influenza virus in cellculture. Other viruses that rely on Hsp90 dependent processes includethose belonging to the families: Herpesviridae (e.g., herpes simplexvirus-1, herpes simplex virus-2, herpes herpesvirus-5, Kaposi'ssarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barrvirus), Polyomaviridae (e.g., SV40), Poxviridae (e.g., vaccinia virus),Reoviridae (e.g., rotavirus), Birnaviridae (e.g., infectious bursaldisease virus), Picornaviridae (e.g., poliovirus, rhinovirus, orcoxsackievirus), Flaviviridae (e.g., hepatitis C virus or dengue virus),Arenaviridae (e.g., lymphocytic choriomeningitis virus), Hepeviridae(e.g., Hepatitis E virus), Rhabdoviridae (e.g., vesicular stomatitisvirus), Paramoxyviridae (e.g., human parainfluenza virus 2, humanparainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus),Bunyaviridae (e.g., La Crosse virus), Orthomoxyviridae (e.g., influenzaA virus), Filoviridae (e.g., Ebola virus), Retroviridae (e.g., HTLV1 orHIV1), and Hepadnaviridae (e.g., hepatitis B virus). Hsp90 inhibitorshave also been used in vivo for the treatment of fungal infectiousdiseases, e.g., treatment of Candida albicans, Aspergillus fumigates, orPneumocystis jiroveci. Moreover, Hsp90 inhibitors are also useful in thetreatment of bacterial infections, e.g., mycobacteria, anthrax, orbacterial pneumonia. A discussion of the diseases that may be treatedwith Hsp90 inhibitors is provided in the U.S. Patent ApplicationPublication 2011/0201587, the disclosure of which is incorporated hereinby reference in its entirety. Therefore, the compounds of the inventionmay be used according to the method of the invention to treat infectiousdiseases, e.g., viral infections, fungal infections, or bacterialinfections.

Inflammatory and Autoimmune Diseases, Allergy

Hsp90 has been shown to play a role in antigen presentation, activationof lymphocytes, macrophages, maturation of dendritic cells, and in theenhanceosome mediated induction of inflammation. Hsp90 inhibition isassociated with blockage of components of inflammation, e.g., reductionof cytokine and NO production, as well as blockage of NFκB nucleartranslocation. Further, considerable body of work indicates thatchaperones, such as Hsp90, may be capable of inducing the production ofproinflammatory cytokines by the monocyte-macrophage system and theactivation and maturation of dendritic cells via the TLR2- and 4-signaltransduction pathways. Thus, Hsp90 apparently can function as a potentactivator of the innate immune system. Indeed, elevated levels of Hsp90were detected in the serum of systemic lupus erythematosus patients.Autoantibodies and cells reactive to Hsp have been detected in patientswith rheumatoid arthritis. Antiinflammatory effect of inhibiting Hsp90was also observed to reduce airway inflammation in murine model ofasthma. The compounds of the invention may be applicable to thetreatment of inflammatory or autoimmune diseases in a patient. Moreover,anti-inflammatory effect of Hsp90 inhibition can have therapeuticapplication in the treatment of allergies. Thus, the compounds of theinvention may be used in the treatment of allergy.

Cardiovascular Diseases

Hsp90 has recently been implicated in etiology of cardiovasculardisorders, such as atherosclerosis and cardiomyopathy. Thus, thecompounds of the present invention may be applicable to the treatment ofcardiovascular diseases (e.g., atherosclerosis or cardiomyopathy).

Kits of the Invention

The present invention also provides kits containing (i) a pharmaceuticalcomposition of the invention, and (ii) instructions for use of thepharmaceutical composition to treat a disorder in a mammal caused by theaction of Hsp90, e.g., a neurodegenerative disorder, a proliferativedisorder, or an infectious disease, as described herein. Kits of theinvention may include instructions explaining how a practitioner (e.g.,a physician, a nurse, a care-giver, or a patient) may administer thecomposition contained therein. The pharmaceutical composition within thekit of the invention may be provided in a container (e.g., a bottle, anampule, a tube, or a blister pack). Furthermore, the kits may alsoinclude additional components, e.g., instructions or administrationschedules for a patient suffering from a neurodegenerative disease or aproliferative disease, and optionally, a device(s) for administering thepharmaceutical composition (e.g., a syringe).

The following examples are meant to illustrate the invention. They arenot meant to limit the invention in any way.

EXAMPLES Example 1. Synthesis of the Compounds of the Invention

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(20). A mixture of

5,7-dichloro-2,3-dihydro-1-benzofuran-4-yl boronic acid (233 mg, 1.0mmol), 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (219 mg, 1.3 mmol),sodium carbonate (318 mg, 3.0 mmol), palladiumtetrakis(triphenylphosphine), and dioxane/water (9/5, 14 ml) was stirredat 90° C. under argon for 20 h, then cooled down to room temperature,quenched with brine (25 ml), and extracted with ethyl acetate (30 ml×2).The combined organic layers were dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gelusing cyclohexane/ethyl acetate (100/0 to 30/70, 15 min) to give aproduct as a white solid (230 mg, 72%). ¹H NMR (500 MHz, CDCl₃): δ 8.01(s, 1H), 7.45 (t, J=3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H), 4.83 (s, 2H),4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M+H]⁺: 321.0 (calcd for[C₁₄H₁₀Cl₂N₄O+H]⁺: 321.0).

The following compounds of the invention have been prepared according tothe procedure described herein.

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-N,6-dimethylpyrimidin-2-amine(3).¹H NMR (500 MHz, CDCl₃): δ 7.25 (s, 1H), 6.57 (s, 1H), 5.07 (d, J=10 Hz,1H), 4.68 (t, J=9 Hz, 2H), 3.29 (t, J=9 Hz, 2H), 3.02 (d, J=10 Hz, 3H),2.40 (s, 3H).

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-N,N,6-trimethylpyrimidin-2-amine(4).¹H NMR (500 MHz, CDCl₃): δ 7.25 (s, 1H), 6.51 (s, 1H), 4.67 (t, J=9 Hz,2H), 3.30 (t, J=9 Hz, 2H), 3.20 (s, 6H), 2.40 (s, 3H).

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-6-methylpyrimidin-2-amine(5).¹H NMR (500 MHz, CDCl₃): δ 7.27 (s, 1H), 6.64 (s, 1H), 5.04 (s, 2H),4.68 (t, J=9 Hz, 2H), 3.25 (t, J=9 Hz, 2H), 2.42 (s, 3H).

4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-6-ethylpyrimidin-2-amine(6). ¹H NMR (500 MHz, CDCl₃): δ 7.27 (s, 1H), 6.65 (s, 1H), 5.05 (s,2H), 4.68 (t, J=9 Hz, 2H), 3.26 (t, J=8.5 Hz, 2H), 2.68 (q, J=8 Hz, 2H),1.29 (t, J=7.5 Hz, 3H); LCMS [M+H]⁺: 310.1 (calcd for [C14H13Cl2N3O+H]⁺:310.04).

4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-6-isopropylpyrimidin-2-amine(7). ¹H NMR (500 MHz, CDCl₃): δ 7.28 (s, 1H), 6.66 (s, 1H), 5.04 (s,2H), 4.69 (t, J=9 Hz, 2H), 3.27 (t, J=9 Hz, 2H), 2.87 (m, 1H), 1.28 (d,J=7 Hz, 6H); LCMS [M+H]⁺: 324.02 (calcd for [C15H15Cl2N3O+H]⁺: 324.06).

4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-6-methoxypyrimidin-2-amine(8). ¹H NMR (500 MHz, CDCl₃): δ 7.28 (s, 1H), 6.19 (s, 1H), 4.98 (s,2H), 4.68 (t, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.25 (t, J=9 Hz, 2H); LCMS[M+H]⁺: 311.87 (calcd for [C13H11Cl2N3O2+H]⁺: 312.02).

4-(2,4-Dichloro-5-methoxyphenyl)-5,6-dimethylpyrimidin-2-amine(9). ¹HNMR (500 MHz, CDCl₃): δ 7.47 (s, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.90(s, 3H), 2.42 (s, 3H), 1.95 (s, 3H).

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-5,6-dimethylpyrimidin-2-amine(10).¹H NMR (500 MHz, CDCl₃): δ 7.25 (s, 1H), 4.89 (s, 2H), 4.69 (t, J=9 Hz,2H), 3.25 (m, 1H), 2.88 (m, 1H), 2.42 (s, 3H), 1.93 (s, 3H).

4-(2-chloro-4-fluoro-5-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(11). ¹H NMR (500 MHz, CDCl₃): δ 7.20 (d, J=10.5 Hz, 1H), 6.94 (d, J=9Hz, 1H), 4.99 (s, 2H), 3.90 (s, 3H), 2.91 (t, J=8 Hz, 2H), 2.72 (t,J=7.5 Hz, 2H), 2.08 (m, 2H); LCMS [M+H]⁺: 294.2 (calcd for[C14H13ClFN3O+H]⁺: 294.07).

4-(2,4-Dichloro-5-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(12).¹H NMR (500 MHz, CDCl₃): δ 7.47 (s, 1H), 6.90 (s, 1H), 4.98 (s, 2H),3.91 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.08 (m,2H).

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(13).¹H NMR (500 MHz, CDCl₃): δ 7.25 (s, 1H), 4.69 (m, 2H), 3.38 (m, 1H),2.99-2.81 (m, 4H), 2.49 (m, 1H), 2.17-2.00 (m, 2H).

4-(2,4-dichloro-5-(2-(dimethylamino)ethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(14). ¹H NMR (500 MHz, CDCl₃): δ 7.46 (s, 1H), 6.90 (s, 1H), 4.97 (s,2H), 4.13 (t, J=6 Hz, 2H), 2.91 (t, J=8 Hz, 2H), 2.80 (t, J=6 Hz, 2H),2.71 (t, J=7.5 Hz, 2H), 2.36 (s, 6H), 2.08 (m, 2H); LCMS [M+H]⁺: 367.1(calcd for [C17H20Cl2N4O+H]⁺: 367.10).

4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5,6,7,8-tetrahydroquinazolin-2-amine(15). ¹H NMR (500 MHz, CDCl₃): δ 7.28 (s, 1H), 4.88 (s, 2H), 4.69 (t,J=9 Hz, 2H), 3.21 (m, 1H), 2.89 (m, 1H), 2.78 (m, 2H), 2.44 (m, 1H),2.15 (m, 1H), 1.86 (m, 2H), 1.72 (m, 2H); LCMS [M+H]⁺: 336.1 (calcd for[C16H15Cl2N3O+H]⁺: 336.06).

4-(2,4-Dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(19). ¹H NMR (500 MHz, CDCl₃): δ 8.15 (s, 1H), 7.54 (s, 1H), 7.46 (m,1H), 7.15 (s, 1H), 6.45 (m, 1H), 4.86 (s, 2H), 3.94 (s, 3H).

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(20). ¹H NMR (500 MHz, CDCl₃): δ 8.01 (s, 1H), 7.45 (t, J=3 Hz, 1H),7.34 (s, 1H), 6.46 (m, 1H), 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H),2.94 (m, 1H); LCMS [M+H]⁺: 321.0 (calcd for [C₁₄H₁₀Cl₂N₄O+H]⁺: 321.0).The ¹H NMR spectrum is shown in FIG. 1.

4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine(21). ¹H NMR (500 MHz, CDCl₃): δ 7.32 (s, 1H), 7.22 (d, J=3 Hz, 1H),6.36 (d, J=3 Hz, 1H), 4.81 (s, 2H), 4.72 (m, 2H), 3.40 (s, 3H), 3.34 (m,1H), 2.91 (m, 1H); LCMS [M+H]⁺: 335.0 (calcd for [C15H12Cl2N4O+H]⁺:335.04).

4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine(22). ¹H NMR (500 MHz, CDCl₃): δ 7.33 (m, 2H), 6.40 (d, J=2.5 Hz, 1H),4.80 (s, 2H), 4.70 (m, 2H), 3.72 (d, J=7 Hz, 2H), 3.33 (m, 1H), 2.91 (m,1H), 1.14 (t, J=7.5 Hz, 3H); LCMS [M+H]⁺: 349.1 (calcd for[C16H14Cl2N4O+H]⁺: 349.05).

Ethyl-2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate(23). ¹H NMR (500 MHz, CDCl₃): δ 7.54 (s, 1H), 7.35 (s, 1H), 5.32 (s,2H), 4.70 (m, 2H), 4.37 (m, 2H), 3.35 (m, 1H), 2.92 (m, 1H), 1.38 (t,J=7 Hz, 3H); LCMS [M+H]⁺: 410.0 (calcd for [C17H13Cl2N3O3S+H]⁺: 410.01).

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide(24). ¹H NMR (500 MHz, CDCl₃): δ 7.34 (s, 1H), 7.21 (s, 1H), 5.91 (s,1H), 5.28 (s, 2H), 4.70 (m, 2H), 4.48 (m, 2H), 3.36 (m, 1H), 2.91 (m,1H), 1.26 (t, J=3.5 Hz, 3H); LCMS [M+H]⁺: 409.0 (calcd for[C17H14Cl2N4O2S+H]⁺: 409.02).

Compounds 34 and 36 were prepared according to methods known in the art,e.g., those described herein. The ¹H NMR spectra (CDCl₃) for compounds34 and 36 are provided in FIGS. 2 and 3, respectively.

Compounds 40-48 can be prepared according to methods known in the art,e.g., those described herein.

4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine(49). ¹H NMR (400 MHz, DMSO-d6): δ=7.48 (s, 1H), 7.30 (s, 2H), 6.78 (s,1H), 4.64 (t, J=8.8 Hz, 2H), 3.20 (t, J=8.8 Hz, 2H). LCMS: m/z calcd forC₁₂H₈Cl₃N₃O [M+H]⁺: 316.0; found: 316.0.

4-trifluoromethyl-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine(50). ¹H NMR (400 MHz, DMSO-d6): δ 7.520 (brs, 2H, NH₂), 7.093 (s, 1H),4.655 (t, 2H, J=8.8 Hz), 3.547 (s, 1H), 3.221 (t, 2H, J=8.8 Hz). LCMS:m/z calcd for C₁₃H₈Cl₂F₃N₃O [M+H]⁺: 350.1; found: 350.0.

4-thiomethyl-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine(51). ¹H NMR (400 MHz, DMSO-d6): δ 7.438 (s, 1H), 6.815 (brs, 2H, NH₂),6.549 (s, 1H), 4.633 (t, 2H, J=8.8 Hz), 3.178 (t, 2H, J=8.8 Hz), 2.453(s, 3H). LCMS: m/z calcd for C₁₃H₁₁Cl₂N₃OS [M+H]⁺: 328.2; found: 328.1.

4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidine-2,5-diamine(52). ¹H NMR (400 MHz, DMSO-d6): δ=7.46 (s, 1H), 6.25 (s, 2H), 4.67 (t,J=8.8 Hz, 2H), 4.30 (s, 2H), 3.15-3.07 m, 2H). HPLC/MS: m/z calcd forC₁₂H₉Cl₃N₄O [M+H]⁺: 331.0; found: 331.1.

2-amino-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-4-ol (53).To a flask containing dioxane:1 N NaOH aq. (50:50; 1 mL:1 mL) were added4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine(49) (20 mg, 0.063 mmol), and DABCO (8 mg, 0.069 mmol), at rt. Thereaction was subsequently heated at 80° C. The reaction was cooled down,acidified by addition of 1 N HCl aq. (2 mL), taken up in ethyl acetate(5 mL) and washed with brine (3×5 mL). The organic layer was dried overNa₂SO₄, filtered, and volatiles were evaporated. The residue waspurified by silica gel chromatography using a gradient of DCM:MeOH(100:0 to 90:10). The product was obtained in 77% yield as a whitesolid.

¹H NMR (400 MHz, DMSO-d6): δ=7.39 (s, 1H), 5.57 (s, 1H), 4.62 (t, J=8.8Hz, 2H), 3.20 (t, J=8.8 Hz, 2H). HPLC/MS: m/z calcd for C₁₂H₉Cl₂N₃O₂[M+H]⁺: 298.0; found: 298.1.

Methyl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate(54). To a flask containing4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(20) (20 mg, 0.062 mmol) in DCM (1 mL) were added dry K₂CO₂>3 (30 mg,0.22 mmol), and methyl chloroformate (0.014 mL, 0.186 mmol), at 0° C.The reaction was allowed to stir for 8 h at rt. Afterwards, the reactionwas quenched by addition of 1 N NaOH aq. (1 mL) and stirred at rt for 1h. The reaction was taken up in DCM (10 mL) and washed with sat. NaHCO₃aq. (10 mL). The organic layer was dried over Na₂SO₄, filtered, andvolatiles were evaporated. The residue was purified by silica gelchromatography using a gradient of DCM:MeOH (100:0 to 90:10). Theproduct was obtained in 66% yield as a yellow solid.

¹H NMR (400 MHz, CDCl3): δ=7.61 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H),4.63 (brs, 2H), 3.77 (s, 3H), 3.65 (br s, 1H), 2.85 (br s, 1H). HPLC/MS:m/z calcd for C₁₆H₁₂Cl₂N₄O₃ [M+H]⁺: 379.0; found: 379.1.

1-(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethan-1-one(55). To a flask containing4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(20 mg, 0.062 mmol) in DCM (1 mL) were added dry K₂CO₃ (30 mg, 0.22mmol), and acetyl chloride (0.006 mL, 0.074 mmol), at 0° C. The reactionwas allowed to stir for 8 h at rt. Afterwards, the reaction was quenchedby addition of 1 N NaOH aq. (1 mL) and stirred at rt for 1 h. Thereaction was taken up in DCM (10 mL) and washed with sat. NaHCO₃ aq. (10mL). The organic layer was dried over Na₂SO₄, filtered, and volatileswere evaporated. The residue was purified by silica gel chromatographyusing a gradient of DCM:MeOH (100:0 to 90:10). The product was obtainedin 81% yield as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ=7.57 (s, 1H), 7.23 (s, 1H), 6.55 (s, 1H),4.63 (brs, 2H), 3.45 (brs, 1H), 3.35 (s, 3H), 2.85 (br s, 1H). HPLC/MS:m/z calcd for C₁₆H₁₂Cl₂N₄O₂ [M+H]⁺: 363.0; found: 363.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde(56). To a flask containing dry THF (2 mL), were added dry DMF (0.1 mL)and POCl₃ (0.015 mL, 0.16 mmol), at 0° C. Reaction was stirred at 0° C.for 30 min, under argon, upon which4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(20 mg, 0.062 mmol) in THF (1 mL) was added dropwise. The reaction wasallowed to stir for 8 h warming to rt. To the reaction was then added 1N NaOH aq. (2 mL) and heated to 80° C. for 1 h. The reaction was cooledto rt and taken up in EtOAc (20 mL) and washed with sat. NaHCO₃ aq. (20mL). The organic layer was dried over Na₂SO₄, filtered, and volatileswere evaporated. The residue was purified by silica gel chromatographyusing a gradient of DCM:MeOH (100:0 to 90:10). The product was obtainedin 58% yield as a white solid.

¹H NMR (400 MHz, CDCl3): δ=10.05 (s, 1H), 7.96 (s, 1H), 7.24 (s, 1H),4.63 (brs, 2H), 3.31 (brs, 1H), 2.85 (brs, 1H). HPLC/MS: m/z calcd forC₁₅H₁₀Cl₂N₄O₂ [M+H]⁺: 349.0; found: 349.1.

7-bromo-4-(2,4-dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine(57). To a flask containing4-(2,4-dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20mg, 0.065 mmol) in AcOH:tBuOH (50:50, 0.5 mL:0.5 mL) were added LiBr (18mg, 0.22 mmol), and Br₂ (0.011 mL, 0.22 mmol), at 0° C. The reaction wasallowed to stir for 8 h at rt. Afterwards, the reaction was taken up inEtOAc (20 mL) and washed with sat. NaHCO₃ aq. (3×20 mL), and Na₂S₂O₃(10% wt. aq., 20 mL). The organic layer was dried over Na₂SO₄, filtered,and volatiles were evaporated. The residue was purified by silica gelchromatography using a gradient of DCM:MeOH (100:0 to 90:10). Theproduct was obtained in 56% yield as a yellow solid.

¹H NMR (400 MHz, DMSO-d6): δ=7.75 (s, 1H), 7.72 (s, 1H), 7.26 (s, 1H),6.24 (s, 2H), 3.86 (s, 3H). HPLC/MS: m/z calcd for C₁₃H₉BrCl₂N₄O [M+H]⁺:386.9; found: 387.0.

General Procedure for Synthesis of2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamides

Step 1: Synthesis of precursor 2,5-dioxopyrrolidin-1-yl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate.To a flask containing degassed DMF:H₂O (50:50; 2 mL:2 mL) were addedethyl 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (100 mg,0.39 mmol), (5,7-dichloro-2,3-dihydrobenzofuran-4-yl)boronic acid (91mg, 0.39 mmol), NaHCO₃ (82 mg, 0.98 mmol), and Pd(PPh₃)₄ (22 mg, 0.02mmol), at rt. The reaction was subsequently heated at 80° C. for 8 hunder argon. The reaction was cooled down, taken up in ethyl acetate (20mL) and washed with brine (3×20 mL). The organic layer was dried overNa₂SO₄, filtered, and volatiles were evaporated. The residue waspurified by silica gel chromatography using a gradient of DCM:MeOH(100:0 to 90:10). The product ethyl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylatewas obtained in 38% yield as a yellow solid.

Ethyl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate(60 mg, 0.15 mmol) was dissolved in THF (1 mL) and to the flask wasadded 1 N NaOH aq. (1 mL). The reaction was stirred for 8 h at rt.Subsequently, the solution was cooled to 0° C. and acidified by additionof 1 N HCl aq. (2 mL), resulting in formation of white precipitate,which was filtered and dried, affording2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylicacid in quantitative yield, without further purification. The filtrand(57 mg, 0.15 mmol) was dissolved in dry DMF (1 mL), cooled to 0° C., andto the reaction vessel were added N-hydroxysuccinimide (23 mg, 0.2 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (38 mg, 0.2 mmol).The reaction was left to stir warming to rt over 8 h. The solution wastaken up into DCM (20 mL) and washed with sat. NH₄Cl aq. (3×20 mL). Theorganic layer was dried over Na₂SO₄, filtered, and volatiles wereevaporated. The residue was purified by silica gel chromatography usinga gradient of DCM:MeOH (100:0 to 90:10). The product2,5-dioxopyrrolidin-1-yl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylatewas obtained as a white solid in 88% yield.

Step 2: General Procedure for Formation of Amides:

To a flask containing the 2,5-dioxopyrrolidin-1-yl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate(10 mg, 0.02 mmol) was added dry DMF (0.5 mL), followed by addition ofan amine (3 eq., 0.06 mmol), (e.g. ammonia, primary amine, or secondaryamine). The reaction was allowed to stir at rt for 12 h, upon which itwas taken up in DCM (5 mL) and washed with sat. NH₄Cl aq. (3×5 mL). Theorganic layer was dried over Na₂SO₄, filtered, and volatiles wereevaporated. The residue was purified by silica gel chromatography usinga gradient of DCM:MeOH (100:0 to 90:10). The resulting amides wereobtained in good to excellent yields.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidine-6-carboxamide(58). ¹H NMR (400 MHz, DMSO-d6): δ=8.79 (s, 1H), 7.61 (s, 1H), 7.58 (s,1H), 7.28 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 3.44-3.11 (m, 6H), 2.90-2.75(m, 4H), 1.77-1.73 (m, 4H). HPLC/MS: m/z calcd for C₂₁H₂₁Cl₂N₅O₂S[M+H]⁺: 478.1; found: 478.1.

2-amino-N-(2-cyanoethyl)-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide(59). ¹H NMR (400 MHz, DMSO-d6): δ=8.94 (t, J=5.6 Hz, 1H), 7.63 (s, 1H),7.60 (s, 1H), 7.34 (s, 2H), 4.69 (t, J=8.8 Hz, 2H), 3.46-3.41 (m, 2H),3.23-3.15 (m, 1H), 3.03-2.97 (m, 1H), 2.76 (t, J=6.4 Hz, 2H). HPLC/MS:m/z calcd for C₁₈H₁₃Cl₂N₅O₂S [M+H]⁺: 434.0; found: 434.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-hydroxyethyl)thieno[2,3-d]pyrimidine-6-carboxamide(60). ¹H NMR (400 MHz, DMSO-d6): δ=8.57 (t, J=5.6 Hz, 1H), 7.59 (s, 2H),7.26 (s, 2H), 4.73 (t, J=5.6 Hz, 1H), 4.67 (t, J=8.8 Hz, 2H), 3.46-3.41(m, 2H), 3.26-3.12 (m, 3H), 3.03-2.94 (m, 1H). HPLC/MS: m/z calcd forC₁₇H₁₄Cl₂N₄O₃S [M+H]⁺: 425.0; found: 425.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-6-carboxamide(61). ¹H NMR (400 MHz, DMSO-d6): δ=9.18 (t, J=6.0 Hz, 1H), 7.72 (s, 1H),7.63 (s, 1H), 7.38 (s, 2H), 4.69 (t, J=8.8 Hz, 2H), 4.12-4.03 (m, 2H),3.26-3.18 (m, 1H), 3.03-2.94 (m, 1H). HPLC/MS: m/z calcd forC₁₇H₁₁Cl₂F₃N₄O₂S [M+H]⁺: 463.0; found: 463.1.

2-amino-N-cyclopropyl-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide(62). ¹H NMR (400 MHz, DMSO-d6): δ=8.54 (s, 1H), 7.61 (s, 1H), 7.53 (s,1H), 7.29 (s, 2H), 4.68 (t, J=8.8 Hz, 2H), 3.26-3.18 (m, 1H), 3.03-2.94(m, 1H), 2.81-2.71 (m, 1H), 0.75-0.61 (m, 2H), 0.55-0.40 (m, 2H).HPLC/MS: m/z calcd for C₁₈H₁₄Cl₂N₄O₂S [M+H]⁺: 421.0; found: 421.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide(63). ¹H NMR (400 MHz, DMSO-d6): δ=8.62-8.59 (m, 1H), 7.61 (s, 2H), 7.27(s, 2H), 4.64 (t, J=8.8 Hz, 2H), 3.24 (s, 3H), 3.23-3.18 (m, 1H),3.03-2.91 (m, 1H). HPLC/MS: m/z calcd for C₁₆H₁₂Cl₂N₄O₂S [M+H]⁺: 395.0;found: 395.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-methoxyethyl)thieno[2,3-d]pyrimidine-6-carboxamide(64). ¹H NMR (400 MHz, DMSO-d6): δ=8.51-8.41 (m, 1H), 7.59 (s, 1H), 7.50(s, 1H), 7.26 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 3.23-3.10 (m, 4H),3.03-2.91 (m, 2H), 2.72-2.67 (m, 3H). HPLC/MS: m/z calcd forC₁₈H₁₆Cl₂N₄O₃S [M+H]⁺: 439.0; found: 439.1.

2-amino-N-cyclobutyl-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide(65). ¹H NMR (400 MHz, DMSO-d6): δ=8.68 (d, J=6.8 Hz, 1H), 7.61 (s, 1H),7.56 (s, 1H), 7.26 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 4.33-4.26 (m, 1H),3.23-3.18 (m, 1H), 3.03-2.91 (m, 1H), 2.16-1.92 (m, 2H), 1.70-1.60 (m,1H), 1.33-1.20 (m, 2H), 0.90-0.78 (m, 1H). HPLC/MS: m/z calcd forC₁₉H₁₆Cl₂N₄O₂S [M+H]⁺: 435.0; found: 435.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylthieno[2,3-d]pyrimidine-6-carboxamide(66). ¹H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.23 (s, 2H), 7.15 (s,1H), 4.66 (t, J=8.8 Hz, 2H), 3.31 (s, 3H), 3.23-2.90 (m, 5H). HPLC/MS:m/z calcd for C₁₇H₁₄Cl₂N₄O₂S [M+H]⁺: 409.0; found: 409.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(oxetan-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide(67). ¹H NMR (400 MHz, DMSO-d6): δ=9.17 (d, J=6.8 Hz, 1H), 7.64 (s, 1H),7.62 (s, 1H), 7.31 (s, 2H), 4.97-4.90 (m, 1H), 4.75-4.65 (m, 4H),4.55-4.45 (m, 2H), 3.20-3.11 (m, 1H), 3.02-2.92 (m, 1H). HPLC/MS: m/zcalcd for C₁₈H₁₄Cl₂N₄O₃S [M+H]⁺: 437.0; found: 437.1.

(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)(morpholino)methanone(68). ¹H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.23 (s, 2H), 7.12 (s,1H), 4.66 (t, J=8.8 Hz, 2H), 3.59 (brs, 8H), 3.26-3.21 (m, 1H),3.02-2.92 (m, 1H). HPLC/MS: m/z calcd for C₁₉H₁₆Cl₂N₄O₃S [M+H]⁺: 451.0;found: 451.1.

(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone(69). ¹H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.23 (s, 2H), 7.21 (s,1H), 4.66 (t, J=8.8 Hz, 2H), 3.68-3.64 (m, 2H), 3.44 (brs, 2H),3.26-3.16 (m, 1H), 3.02-2.92 (m, 1H), 1.91-1.76 (m, 4H). HPLC/MS: m/zcalcd for C₁₉H₁₆Cl₂N₄O₂S [M+H]⁺: 435.0; found: 435.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methyl-N-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-6-carboxamide(70). ¹H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.33 (s, 3H), 4.66 (t,J=8.8 Hz, 2H), 4.41-4.28 (m, 2H), 3.27 (s, 3H), 3.26-3.16 (m, 1H),3.02-2.92 (m, 1H). HPLC/MS: m/z calcd for C₁₈H₁₃Cl₂F₃N₄O₂S [M+H]⁺:477.0; found: 477.1.

2-amino-N-(2-cyanoethyl)-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide(71). ¹H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.28 (s, 2H), 7.20 (s,1H), 4.66 (t, J=8.8 Hz, 2H), 3.69 (brs, 2H), 3.26-3.16 (m, 4H),3.02-2.92 (m, 1H), 2.82-2.70 (m, 2H). HPLC/MS: m/z calcd forC₁₉H₁₅Cl₂N₅O₂S [M+H]⁺: 448.0; found: 448.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methyl-N-(oxetan-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide(72). ¹H NMR (400 MHz, DMSO-d6): δ=7.55 (s, 1H), 7.26 (s, 2H), 7.16 (s,1H), 5.21-5.16 (m, 1H), 4.69-4.60 (m, 6H), 3.26-3.14 (m, 4H), 3.02-2.92(m, 1H). HPLC/MS: m/z calcd for C₁₉H₁₆Cl₂N₄O₃S [M+H]⁺: 451.0; found:451.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-hydroxy-2-methylpropyl)thieno[2,3-d]pyrimidine-6-carboxamide(73). ¹H NMR (400 MHz, DMSO-d6): δ=8.44 (s, 1H), 7.69 (s, 1H), 7.59 (s,1H), 7.23 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 4.45 (s, 1H), 3.21-3.12 (m,3H), 3.02-2.92 (m, 1H), 1.04 (s, 6H). HPLC/MS: m/z calcd forC₁₉H₁₈Cl₂N₄O₃S [M+H]⁺: 453.0; found: 453.1.

2-amino-N-cyclopropyl-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide(74). ¹H NMR (400 MHz, DMSO-d6): δ=7.55 (s, 1H), 7.36 (s, 1H), 7.28 (s,2H), 4.70-4.62 (m, 2H), 3.13-3.06 (m, 1H), 3.00-2.91 (m, 4H), 0.80-0.72(m, 2H), 0.68-0.63 (m, 2H). HPLC/MS: m/z calcd for C₁₉H₁₆Cl₂N₄O₂S[M+H]⁺: 435.0; found: 435.1.

2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide(75). ¹H NMR (400 MHz, DMSO-d6): δ=7.57 (s, 1H), 7.47 (s, 1H), 7.37 (s,2H), 4.70-4.62 (m, 2H), 3.74 (s, 3H), 3.27-3.19 (m, 4H), 3.00-2.91 (m,1H). HPLC/MS: m/z calcd for C₁₇H₁₄Cl₂N₄O₃S [M+H]⁺: 425.0; found: 425.1.

1-(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)propan-1-one(76). To a flask containing2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide(20 mg, 0.048 mmol) in dry THF (1 mL), was added EtMgBr (2.0 M in THF;0.029 mL, 0.057 mmol), at 0° C. The reaction was stirred for 8 h, uponwhich it was quenched by addition of sat. NH₄Cl aq (1 mL). The aqueouslayer was extracted with EtOAc (3×2 mL), dried over Na₂SO₄, filtered,and volatiles were evaporated. The residue was purified by silica gelchromatography using a gradient of DCM:MeOH (100:0 to 90:10). Theproduct was obtained in 91% yield as a white solid.

¹H NMR (400 MHz, CDCl₃): δ=7.41 (s, 1H), 7.34 (s, 1H), 5.84 (br s, 2H),4.74-4.64 (m, 2H), 3.87-3.76 (m, 1H), 3.30-3.10 (m, 3H), 1.50-1.41 (m,3H). HPLC/MS: m/z calcd for C₁₇H₁₃Cl₂N₃O₂S [M+H]⁺: 394.0; found: 394.1.

2-(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)propan-2-ol(77)

To a flask containing ethyl2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate(20 mg, 0.048 mmol) in dry THF (1 mL), was added MeMgBr (2.0 M in THF;0.072 mL, 0.144 mmol), at 0° C. The reaction was stirred for 8 h, uponwhich it was quenched by addition of sat. NH₄Cl aq (1 mL). The aqueouslayer was extracted with EtOAc (3×2 mL), dried over Na₂SO₄, filtered,and volatiles were evaporated. The residue was purified by silica gelchromatography using a gradient of DCM:MeOH (100:0 to 90:10). Theproduct was obtained in 78% yield as a white solid.

¹H NMR (400 MHz, DMSO-d6): δ=7.53 (s, 1H), 6.85 (s, 2H), 6.54 (s, 1H),5.95 (s, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.20-3.12 (m, 1H), 3.00-2.90 (m,1H), 1.46 (s, 3H), 1.44 (s, 3H). HPLC/MS: m/z calcd for C₁₇H₁₅Cl₂N₃O₂S[M+H]⁺: 396.0; found: 396.1.

Example 2. In Vitro Assays of the Compounds of the Invention

Hsp90 Biochemical Assay (Fluorescence Polarization)

Hsp90 inhibitory activity of the compounds of the invention was assessedusing a fluorescence polarization (FP) assay using FITC-labeledgeldanamycin and truncated alpha-Hsp90 protein. Measurement of bindingactivity was performed on BMG CLARIOstar® reader (BMG Labtech,Ortenberg, Germany). This assay is homogeneous and is performed in384-well plates performing consistently with known standards. The assaywas validated with known Hsp90 inhibitors, e.g., PU-H71 (IC₅₀=60 nM),which is in agreement with the reported IC₅₀ (Luo et al., supra). Theresults of this assay for compounds 20, 36, 37, and 39 and for the knownHsp90 inhibitor are shown in FIG. 4.

Hsp90 Biochemical Assay (AlphaLISA)

Hsp90 inhibitory activity of the compounds of the invention was assessedusing a robust and reproducible assay based on the AlphaLISA format wasdeveloped (PerkinElmer, Inc., Waltham, Mass.; the format of the assay isdescribed in, e.g., ELISA to AlphaLISA Conversion Guide, PerkinElmer,Inc., published in August, 2012). This assay employs biotinylatedgeldanamycin, His-tagged-Hsp90, and Ni⁺² coated beads. This assay ishomogenous and miniaturized to 384-well plates. Measurement of bindingactivity was performed on an Envision reader. The assay was validatedwith known Hsp90 inhibitors, including PU-H71 (IC₅₀=60 nM) which is inagreement with the reported IC₅₀ (Luo et al., supra). This assay is theprimary assay for evaluating compounds of the invention. In this assay,compound 20 showed Hsp90 inhibitory activity (IC₅₀ of 0.74±0.1 μM; seeFIG. 5A).

Hsp90 Cell Based Functional Assays

Cells were treated with compounds of the invention for 24 h and thenlysed in a buffer containing NP-40, orthovanadate, and proteaseinhibitors. Western blots were performed with antibodies specific toHsp70, Hsp90, or actin (as control). Tau phosphorylation was assayedusing, e.g., a method of Liu et al., Biochemistry, 49:4921-4929, 2010,with SHSY5Y-hTau441V337M/R406W cell line (Loeffler et al., J. Mol.Neurosci., 47:192-203, 2012). This cell line represents stabletransfected cell line that has been shown to have hyper-phosphorylatedtau by over-express the longest human tau isoform, hTAU441 with twomutations: V337M and R406W. The functional assay described hereinprovides an in vitro model of tauopathy and can be used to evaluate theeffect of Hsp90 inhibitors on phosphorylated tau protein (p-Tau). Inthese assays, compound 20 showed increase in the expression of Hsp70(see FIG. 5B), significant decreases in the levels of pTau231 at 0.1 and0.5 μM (see FIG. 6B), and significant decreases in the levels of pTau396at 0.05, 0.1, and 0.5 μM (see FIG. 6C).

Cytotoxicity Assays

SH-SY5Y-hTAU441 cell viability was determined using the MTT assay. Asshown in FIG. 6A, compound 20 did not affect cell viability ofSH-SY5Y-hTAU441 cells. SH-SY5Y cell viability may also be measured after24 and 48 h with the CellTiter-Glo® assay that measures ATP-levels. Inaddition, cytotoxicity may be assessed using the Celigo® with live cellmicroscopic imaging and a GE InCell Analyzer 2000 to measure multipleoutcomes including apoptosis markers, membrane permeability, andmitochondrial activity.

Mouse Liver Microsomal Stability

Metabolic stability of the compounds of the invention was assessed bymonitoring their degradation in mouse liver microsomes. Compound 20demonstrated good microsomal stability (T_(1/2)=26 min).

Solubility

Compound solubility was determined in pH 7.4 buffer. Aqueous solubilityof greater than or equal to about 0.5 μM (e.g., greater than or equal toabout 1 μM, greater than or equal to about 2 μM, greater than or equalto about 5 μM, greater than or equal to about 10 μM, greater than orequal to about 20 μM, or greater than or equal to about 30 μM) mayindicate a compound having acceptable solubility for medical use, e.g.,for treatment of a neurodegenerative disorder. At pH of 7.4, compound 20exhibits an aqueous solubility of 30 μM.

Cell Permeability

Compounds may be assessed in MDR1-MDCK permeability assay or Caco-2permeability assay to determine their permeability. Apical (A) to basal(B) permeability >3×10⁻⁶ cm/sec and B→A/A→B asymmetry <3 for a compoundare considered acceptable predictors of brain penetration, and compoundshaving such properties are unlikely to be P-glycoprotein (P-gp)substrates. Compound 20 has shown excellent permeability in MDR1-MDCKassay (A−B=28×10⁻⁶ cm/s) with low asymmetry (B→A/A→B asymmetry=0.9).

Results of the above-described assays for certain compounds of theinvention are summarized in Table 3.

TABLE 3 Hsp90 Hsp 70 inhibitory agonist Compound MW cLogP PSA activityactivity 1

317 4 60 − 2

311 4.3 60 ++ 3

309 3.9 46 − 4

323 4.7 37 − 5

295 3.6 60 +++ >2 fold at 0.4- 1.0 μM 6

310 4.1 60 +++ ≥10 μM 7

324 4.5 60 +++(1) — 8

312 3.5 69 +++(2) — 9

298 3.5 60 +++(3) 1.5-fold at 1 μM 10

310 3.9 60 +++(4) >2-fold at 0.4 μM 11

293 3.7 60 + 12

310 3.9 60 +++(5) >2-fold at ≥10 μM 13

322 4.2 60 +++(6) — 14

367 4.1 63 +++ 2-fold at 10 μM 15

336 4.5 60 + 16

323 17

394 − 18

333 19

309 3.8 72 +++ >2-fold at 0.4- 1 μM 20

321 4.1 72 +++ — 21

335 3.1 63 ++ — 22

349 3.4 63 + — 23

410 4.8 86 +(7) 3.3 μM 24

409 4.1 89 +++ 0.4 μM 25

292.70 2.5 72 +(8) 1.5 fold, or no observable effect 26

306.73 2.7 63 ++(9) 2 fold at 3.3 μM, or no observable effect 27

366.25 2.9 75 ++ 10 μM 28

324.21 4.5 60 − 29

381.23 3.6 103 +++ 0.4 μM 30

335.19 3.4 63 − 31

406.27 2.3 92 − 32

406.27 2.6 92 − 33

311.17 3.1 72 + 34

317.19 4.5 72 +++ 3.3 μM; 10 μM 35

316.20 4.0 60 +++ 3.3 μM; 10 μM 36

301.13 3.9 82 +++ >10 μM 37

446.11 7.0 82 − 38

284.14 3.6 60 ++ 39

304.56 3.8 60 +++ 0.4 μM 49

316.6 3.8 60 +++ 50

350.1 4.0 60 ++ 51

328.2 4.0 60 +++ 52

331.6 3.0 86 +++ 53

298.1 3.2 80 − 54

379.2 3.4 90 − 55

363.2 2.8 80 − 56

348.0 2.6 89 − 57

388.1 3.7 72 − 58

478.4 4.1 9.2 +++ 59

434.3 3.8 113 +++ 60

425.3 3.3 109 +++ 61

463.3 4.8 89 +++ 62

421.3 4.1 89 +++ 63

395.3 3.8 89 +++ 64

439.3 3.6 98 +++ 65

435.3 4.5 89 +++ 66

409.3 4.0 80 +++ 67

437.3 3.4 98 +++ 68

451.3 3.6 89 ++ 69

435.3 4.3 80 ++ 70

477.3 5.0 89 + 71

448.3 4.1 104 +++ 72

451.3 3.6 89 ++ 73

453.3 3.8 109 +++ 74

435.3 4.3 80 ++ 75

425.3 89 +++ 76

394.3 4.6 77 +++ 77

396.3 4.6 80 ++ 78

269.01 ++ 79

269.01 +++ In Table 3, “Hsp90 inhibitory activity” provides anassessment of exemplary compounds for their ability to inhibit Hsp90. Inparticular, “−” indicates that the compound has IC₅₀ of greater thanabout 10 μM, “+” indicates that the compound has IC₅₀ in the range ofabout 4 μM to about 10 μM; “++”indicates that the compound has IC₅₀ inthe range of about 1 μM to about 4 μM; “+++” indicates that the compoundhas IC₅₀ of less than about 1 μM. “Hsp 70 agonist activity” indicatesEC₅₀ (μM) of the exemplary compound at which Hsp70 is increased two-foldunless otherwise noted; “—” designates lack of observable effect atconcentrations exceeding 10 μM. (1)Data according to AlphaLISA assay, FPassay result: >10 μM. (2)Data according to AlphaLISA assay, FP assayresult: 5.5 and 6.2 μM. (3)Data according to AlphaLISA assay, FP assayresult: 1 and 1.4 μM. (4)Data according to AlphaLISA assay, FP assayresult: 2.3 and 2.4 μM. (5)Data according to AlphaLISA assay, FP assayresult: 1.7 μM. (6)Data according to AlphaLISA assay, FP assay result:1.8 μM. (7)Data according to AlphaLISA assay, FP assay result: 11.1 μM.(8)Data according to AlphaLISA assay, FP assay result: 12.1 and 19.3 μM.(9)Data according to AlphaLISA assay, FP assay result: 8.5 and 11.2 μM.

Example 3. Pharmacokinetic Properties of the Compounds of the Invention

The pre-clinical study included 85 mice, distributed over 6 groups; asummary of treatment groups is given in Table 4.

TABLE 4 Group n Sacrificed at Sample reference A 5 Pre-dose A_0 B 3 15minutes B_0.25 C 3 30 minutes C_0.5 D 3 1 hour D_1 E 3 2 hours E_2 F 3 8hours F_8

Plasma and brain samples were taken pre-dose and at post dose timepoints of pre-dose, 15 and 30 minutes, 1, 2, and 8 hours. The pre-dosegroup was represented by 5 animals, whereas the post-dose groups wererepresented by 3 animals.

Bioanalysis Methods

Bioanalysis of mouse plasma samples for compound 20 was conducted byprotein precipitation and LC-MS/MS with compound 22 as the internalstandard. The method was based on a ‘generic assay’ and some methoddevelopment was conducted to tailor that assay to the particularcompound and internal standard. The eventual non-GLP assay was firsttested by analyzing a bioanalytical run with spiked mouse plasmasamples. The qualification run passed by the run acceptance criteria(see below).

Bioanalysis was then conducted of plasma sample extracts and of brainsample homogenate extracts, using a calibration and quality controlsamples spiked in mouse plasma. The assay is described below.

Assay of Mouse Plasma Levels of Compound 20

Sample Treatment

Compound 20 and compound 22 were extracted from the mouse plasma matrixby protein precipitation. To 20.0 μL of sample was added 10.0 μL ofinternal standard working solution (1000 ng/mL in MeOH) and 200 μL ofMeCN. The mixture was vortexed (˜5 sec) and centrifuged (14000 rpm, 5min). The supernatant was then recovered and evaporated to dryness. Theresidue was redissolved in 100 μL of redissolving solution (80:20 v:v ofmobile phases A:B). For analysis, 20.0 μL was injected in to theLC-MS/MS system.

Chromatography

All chromatography was done with a type 1100 liquid chromatograph(Agilent), equipped with an auto-injector. The analytical column was anXbridge C18 3.5 μm 2.1×50 mm (Waters), employed at 50° C. The mobilephase was a gradient, composed of solvent A: 1 g/L ammonium acetate inMilli-Q water, and solvent B: MeCN. The gradient was as shown in Table5.

TABLE 5 Flow rate Step Total time (min) (μL/min) A (%) B (%) 0 0.00 70080 20 1 0.20 700 80 20 2 1.00 700 0 100 3 2.00 700 0 100 4 2.10 700 8020 5 5.00 700 80 20

Mass Spectrometry

All experiments were done on an API 3000 triple quadrupole instrument(AB Sciex), operated in positive turbo-ionspray mode (‘TIS+’). Theinstrument parameters had been optimized during method development. TheMS/MS transitions employed were as shown in Table 6.

TABLE 6 Q1, [M + H] + (35Cl2) Q3 [M + H—HCl] + (35Cl2) Compound (Da)(Da) Compound 20 321.1 285.0 Compound 22 349.2 318.9

Description of Bioanalytical Experiment and Acceptance Criteria

The calibration range for compound 20 was set up to cover concentrationsbetween 0.988 and 20000 ng/mL. Two sets of calibration samples wereused, one set placed before and the other placed after the studysamples. In addition, QC samples at 5 levels (two samples at each level)were included in the run, as performance indicators and for runacceptance.

Acceptance criteria for calibration and QC samples were applied, asfollows:

-   -   The absolute % RE (% RE) relative to the nominal concentration        for individual calibration and QC samples should be within 20%        (or 25% at LLOQ);    -   A calibration level was considered valid when at least one of        the calibration samples at that concentration level was accepted        by the above |% RE| criterion;    -   A QC level was considered valid when at least one of the QC        samples at that concentration level was accepted by the above %        RE criterion.

The lowest and highest accepted calibration concentration levels wereadopted as the lower and upper limit of quantification, LLOQ and HLOQ,respectively.

Bioanalytical Results

For compound 20, the highest calibration level (STD L, 20000 ng/mL) didnot pass acceptance criteria as both calibration samples displayed toohigh a bias (see Table 7). All other calibration levels of compound 20,STD A through STD K, were accepted with single samples at STD C and STDG displaying too high bias. As a consequence, the lowest level (STD A,0.988 ng/mL) was adopted as the LLOQ and the next higher level (STD K,8000 ng/mL) was adopted as the HLOQ. One of the QC LLOQ and one of theQC Med sample results had too high a bias. The overall methodperformance in the bioanalytical run was accepted for compound 20.

Calibration and QC concentration levels employed are shown in Table 7:

TABLE 7 Compound 20 concentration Sample indicator (ng/mL) STD A 0.988STD B 2.37 STD C 5.93 STD D 14.8 STD E 35.6 STD F 88.9 STD G 222 STD H533 STD I 1333 STD J 3333 STD K 8000 STD L 20000 QCLLQ 2.37 QCLow 14.8QCMed 88.9 QCHigh 1333 QCOC 8000

The bioanalysis results for plasma and brain samples are presented inTables 8 and 9.

TABLE 8 Concentration compound 20 Group IRN (ng/mL) A_0 2      0.00 ^(a)A_0 4    2.16 A_0 6      0.00 ^(a) A_0 8      0.00 ^(a) A_0 10      0.00^(a) B_0.25 12    2.66 B_0.25 14  17,900 ^(b) B_0.25 16  12,000 ^(b)C_0.5 18  11,500 ^(b) C_0.5 20  10,500 ^(b) C_0.5 22  11,100 ^(b) D_1 246,890 D_1 26 7,130 D_1 28 7,470 E_2 30 4,150 E_2 32 4,180 E_2 34 4,440F_8 36   99.3 F_8 38   22.5 F_8 40   21.9 ^(a) “0.00” represents ‘belowlimit of quantification’ (LLOQ; the LLOQ was 0.988 ng/mL). ^(b) Value isout of range (0.988-8000 ng/mL); two calibrators at 20000 ng/mL wererejected but showed an average response of 14000 ng/mL.

TABLE 9 Homogenate Brain concentration concentration Brain weight ofcompound 20 Group IRN (ng/mL) (g) (ng/g) A_0 2     0.00 ^(a) 0.453    0.00 ^(a) A_0 4     0.00 ^(a) 0.483     0.00 ^(a) A_0 6     0.00^(a) 0.451     0.00 ^(a) A_0 8     0.00 ^(a) 0.487     0.00 ^(a) A_0 10    0.00 ^(a) 0.472     0.00 ^(a) B_0.25 12     0.00 ^(a) 0.463     0.00^(a) B_0.25 14 2300  0.445 20674  B_0.25 16 1250  0.460 10870  C_0.5 181400  0.482 11618  C_0.5 20 844 0.458 7371 C_0.5 22 1200  0.458 10480 D_1 24 888 0.474 7494 D_1 26 859 0.459 7486 D_1 28 789 0.461 6846 E_2 30410 0.455 3604 E_2 32 385 0.461 3341 E_2 34 294 0.467 2518 F_8 36   7.53 0.478    63.0 F_8 38    1.83 0.489    15.0 F_8 40    1.53 0.476   12.9 ^(a) “0.00” represents “below limit of quantification” (LLOQ;the LLOQ was 0.988 ng/mL).

In the plasma samples, the following observations were made:

-   -   There was one minor response in a pre-dose sample (one A_0        sample; found at 2.16 ng/mL). This response may have come from a        minor contamination or from assay interference. Although        selectivity of LC-MS/MS methods is generally high, selectivity        for compound 20 in plasma was not tested. Conclusions can only        be drawn after more elaborate method qualification or even        method validation. At less than 3 times LLOQ, this pre-dose        response is considered negligible here.    -   Results for most measurements in time point B_0.25 and all        measurements in time point C_0.5 are above the upper limit of        quantification (ULOQ, at 8000 ng/mL). For obtaining more        reliable results, these samples would have to be diluted prior        to analysis. It is noted that a highest calibrator at 20000        ng/mL was included in the run but failed on bias. The mean        back-calculated concentration of 20000 ng/mL was 14000 ng/mL,        indicating a bias of −30% at that level. The above ULOQ results        were included in this Example as indicative values, in support        of PK evaluation. However, the results from B_0.25 and C_0.5        time points should be treated with caution.    -   Results from the first subject in the time point B_0.25 (IRN 12)        are unlikely to be near the observed 2.66 ng/mL, as that does        not match with the relatively high concentrations observed in        the other two subjects at this first post-dose time point (IRN        14 and 16). Provisionally, PK evaluation for this time point was        conducted for both cases: (1) mean of 3 and (2) mean of two with        exclusion of this BLOQ result.

In the brain (homogenate) samples one result appear different fromexpectation:

-   -   results from the first subject in the time point B_0.25 (IRN 12)        are unlikely to be below LLOQ, as that does not match with the        relatively high concentrations observed in the other two        subjects at this first post-dose time point (IRN 14 and 16).        Please note that this parallels the findings for plasma from        this subject (IRN 12). Provisionally, PK evaluation for this        time point was conducted for both cases: (1) mean of 3 and (2)        mean of two with exclusion of this BLOQ result.

Pharmacokinetic Evaluation

Evaluation of pharmacokinetic parameters was conducted by calculationfrom the mean concentration (n=5 pre-dose, n=3 post-dose) at each timepoint. The pharmacokinetic results are summarized below.

Mouse Plasma

Results for pharmacokinetic evaluation are given in Tables 10-12 andFIGS. 7 and 8. No corrections were made for results above the ULOQ orfor the inclusion of the result for animal IRN12 in group B_0.25.

TABLE 10 Mean Group Concentration Group Time Point (h) (ng/mL) A_0 0.00    0.432 B_0.25 0.25   9968 ^(a) C_0.5 0.50 11033  D_1 1.00 7163 E_22.00 4257 F_8 8.00    47.9 ^(a) Excluding IRN 12 result: 14950 ng/mL

Tables 11 and 12 provide plasma pharmacokinetic profile of compound 20.

TABLE 11 ^((a)) Parameter Value Unit C_(max) 11033 ng/mL T_(max) 0.50hours (h) K_(elimination) 0.725 per hour (h⁻¹) Half life (t_(1/2)) 0.96hours (h) AUC(0-8 h) 27044 ng/mL · h AUC(0-inf) 27055 ng/mL · h ^((a))excluding IRN12 result.

TABLE 12 ^((a){) Parameter Value Unit C_(max) 14950 ng/mL T_(max) 0.25hours (h) K_(elimination) 0.730 per hour (h⁻¹) Half life (t_(1/2)) 0.95hours (h) AUC(0-8 h) 28290 ng/mL · h AUC(0-inf) 28301 ng/mL · h ^((a){)including IRN12 result.

Mouse Brain Tissue

Results for brain tissue pharmacokinetic evaluation are given in FIGS. 9and 10 and Tables 13-15. No corrections were made for the inclusion ofthe odd result for animal IRN 12 in group B_0.25.

TABLE 13 Mean Group Concentration Group Time Point (h) Homogenate(ng/mL) Tissue (ng/g) A_0 0.00 0.00     0.00 B_0.25 0.25 1183  10515^(a) C_0.5 0.50 1148 9823 D_1 1.00 845 7275 E_2 2.00 363 3154 F_8 8.003.63    30.0 ^((a)) excluding IRN 12 result: 15772 ng/g.

Tables 14 and 15 provide brain tissue pharmacokinetic profile ofcompound 20.

TABLE 14 ^((a)) Parameter Value Unit C_(max) 10515 ng/mL T_(max) 0.25hours (h) K_(elimination) 0.769 per hour (h⁻¹) Half life (t_(1/2)) 0.90hours (h) AUC(0-8 h) 22898 ng/mL · h AUC(0-inf) 22908 ng/mL · h ^((a))excluding IRN 12 result.

TABLE 15 ^((a)) Parameter Value Unit C_(max) 15772 ng/mL T_(max) 0.25hours (h) K_(elimination) 0.789 per hour (h⁻¹) Half life (t_(1/2)) 0.88hours (h) AUC(0-8 h) 24212 ng/mL · h AUC(0-inf) 22908 ng/mL · h ^((a))including IRN 12 result.

Example 4. Effect of the Compounds of the Invention on the Total Levelof Tau and Level of p-Tau in Cerebrospinal Fluid (CSF) and Brain in theTau Transgenic Mouse Model (hTAU441)

To assess the effect of the compounds of the invention on p-tauaccumulation, age-matched (e.g., 5 month old) transgenic mice humanizedfor the tau gene (hTAU mice) may be treated with low- or high-dose of acompound of the invention or vehicle by intraperitoneal administrationfor 7 days (N=6 per arm). Dose of the compound of the invention may becalculated based on the PK results. hTAU transgenic mice (C₅₇BL/6background) over-express TAU441 bearing the missense mutations V337M andR406W under the control of the brain specific murine Thy-1 promoter.This human mutated tau isoform is expressed in high levels and the taupathology and is visible at an early age starting at four months.Severity of the brain pathology correlates with increasing age andbehavioral deficits, whereas no motor deficits occur. All animals may besacrificed and quantified for soluble and insoluble tau and p-tau brain(hippocampus and cortex) using MSD multiarray p-tau (ThR²¹1)immunosorbent assay (Meso Scale Discovery, Rockville, Md.) to establishtotal tau and p-tau levels in CSF and Hsp70 levels in brain extracts.Specifically, the animals may be anaesthetized with ketamine/xylazin mix(note: isoflurane is known to influence p-tau levels), kept warm and ina horizontal position, prior to and during the collection of CSFfollowed by blood. The volume of CSF collected in hTAU441 is only 2-6μL/mouse compared to some strains (2-15 μL/mouse). p-Tau (ThR²¹1) andtotal tau levels may be assessed using phospho-PHF-Tau pThR²¹1 (MSDduplex kit, Meso Scale Discovery, Rockville, Md.).

Administration of a compound of the invention may lead to a decrease inp-tau levels in mice treated with a compound of the invention relativeto p-tau levels in mice administered a vehicle.

Example 5. Effect of the Compounds of the Invention on Memory andLearning in the hTAU441 Transgenic Mouse Model

Five month old transgenic hTAU mice described in Example 3 may beadministered intraperitoneally a low- or high-dose of a compound of theinvention groups or a vehicle daily for 12 weeks (N=15 per arm). Acorresponding untreated group of mice will be analyzed as baseline.Behavioral testing, e.g., Probe Trial, Nose Poke Curiosity and ActivityTest, and the Morris Water Maze task may be performed. Upon completionof the study, CSF may be collected and brain tissue may be harvestedfrom these animals. Total tau levels and p-tau levels may be assessed inthe CSF and brain. Additionally, immunohistochemical determination oftau pathology may be conducted. Tau depositions may be determined usingthe monoclonal antibodies AT180 (Thermo Scientific Pierce Antibodies,Rockford, Ill.) and HT7 (Thermo Scientific Pierce Antibodies, Rockford,Ill.). Sodium selenate, a PP2A phosphatase activator thatdephosphorylates tau and reverses memory deficits, is effective in theTMHT tau model (Corcoran et al., J. Clin. Neuroscience, 17:1025-1033,2010).

If chronic treatment with a compound of the invention is associated witha general improvement in memory function as measured by the Morris Maze,reduced levels of p-tau in the brain may be observed.

OTHER EMBODIMENTS

The invention is also described by the following numbered embodiments:

1. A compound according to formula (I):

or a pharmaceutically acceptable salt thereof,where

-   -   Z¹ is —OR⁷, —N(R¹⁰)R⁷, —SR⁷, or —C(R¹⁰)(R¹¹)R⁷;    -   Z² is —N═ or —C(R³)═;    -   each R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   R³ is H, halogen, cyano, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₃ alkoxy, or optionally substituted        amino, and R⁴ is halogen, cyano, optionally substituted C₁₋₆        alkyl, optionally substituted C₁₋₃ alkoxy, optionally        substituted amino, optionally substituted C₁₋₆ thioalkoxy, or        optionally substituted C₆₋₁₀ aryl, or R³ and R⁴, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally including one        nitrogen, one oxygen, or one sulfur, where the nitrogen is        optionally substituted with R⁹;    -   each R⁵ and R⁶ is, independently, H, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five- or six-membered ring        optionally including one or two heteroatoms selected from        nitrogen, oxygen, and sulfur;    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl;    -   R¹⁰ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl, and R¹¹ is H, optionally substituted        C₁₋₃ alkyl, or R¹⁰ and R¹¹ combine to form ═O or ═S;    -   R^(m) is H, halogen, optionally substituted C₁₋₄ alkyl, or        optionally substituted C₁₋₃ alkoxy; where,    -   when Z² is CR³, each of R¹ and R² is H, R³ is H, R⁴ is methyl or        chloro, and each of R⁵ and R⁶ is chloro,    -   Z¹ is not methoxy;    -   when Z² is N, each of R⁵ and R⁶ is chloro, R³ is H, R⁴ is        substituted C₁₋₆ thioalkoxy,    -   Z¹ is not cyanomethoxy or aminomethoxy;    -   when Z² is CR³, each of R⁵ and R⁶ is chloro, R³ is H, and R⁴ is        halogen,    -   Z¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy;    -   when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)ethyl, difluoromethyl, or        2-(t-butylamino)ethyl;    -   when each R⁵ and R⁶ is bromo, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IIa),    -   R⁷ is not methyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IIa),    -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, R⁷ and R⁸ combine to        form —CH₂—CH₂—, and R³ and R⁴ combine to form a group according        to formula (IIa),    -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl    -   when R⁵ is methoxy, R⁶ is methyl, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIa),    -   R⁷ is not methyl;    -   when R⁵ is chloro, R⁶ is ethyl, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIa),    -   R⁷ is not methyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IIb) or (IIc),

-   -   R⁷ is not methyl or 2-(N,N-diethylamino)ethyl;    -   when R⁷ is methyl, R⁵ is chloro, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIIa),

-   -   R⁶ is not bromo;    -   when R⁵ is chloro, R⁶ is methoxy, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIIb):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVa):

-   -   R⁷ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVb):

-   -   R⁷ is not 2-methoxyethyl or benzyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVc):

-   -   R⁷ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVd):

-   -   R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVe) or (IVf):

-   -   R⁷ is not benzyl;    -   when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IVg), (IVh),        (IVi), (IVj), or (IVk):

-   -   R⁷ is not methyl;    -   when R⁶ is methyl,    -   each R¹ and R² is H; and    -   when R³ is H, Z¹ is —OR⁷, and each R⁵ and R⁶ is chloro,    -   R⁷ is not methyl.

2. The compound of embodiment 1, where R^(m) is H.

3. A compound according to formula (Ia):

or a pharmaceutically acceptable salt thereof,where

-   -   each R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   R³ is H, halogen, cyano, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₃ alkoxy, or optionally substituted        amino, and R⁴ is halogen, cyano, optionally substituted C₁₋₆        alkyl, optionally substituted C₁₋₃ alkoxy, optionally        substituted amino, optionally substituted C₁₋₆ thioalkyl, or        optionally substituted C₆₋₁₀ aryl, or R³ and R⁴, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally including one        nitrogen, one oxygen, or one sulfur, where the nitrogen is        optionally substituted with R⁹;    -   each R⁵ and R⁶ is, independently, H, optionally substituted C₁₋₃        alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five- or six-membered ring        optionally including one or two heteroatoms selected from        nitrogen, oxygen, and sulfur;    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl;    -   Z¹ is —OR⁷, —N(R¹⁰)R⁷, —SR⁷, or —C(R¹⁰)(R¹¹)R⁷; and    -   R¹⁰ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl, and R¹¹ is H, optionally substituted        C₁₋₃ alkyl, or R¹⁰ and R¹¹ combine to form ═O or ═S;        where,    -   when each of R¹ and R² is H, R³ is H, R⁴ is methyl or chloro,        and each of R⁵ and R⁶ is chloro,    -   Z¹ is not methoxy;    -   when each of R⁵ and R⁶ is chloro, R³ is H, and R⁴ is halogen,    -   Z¹ is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy,        methoxy, or benzyloxy;    -   when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)ethyl, difluoromethyl, or        2-(t-butylamino)ethyl;    -   when each R⁵ and R⁶ is bromo, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IIa),    -   R⁷ is not methyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IIa),    -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, R⁷ and R⁸ combine to        form —CH₂—CH₂—, and R³ and R⁴ combine to form a group according        to formula (IIa),    -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl    -   when R⁵ is methoxy, R⁶ is methyl, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIa),    -   R⁷ is not methyl;    -   when R⁵ is chloro, R⁶ is ethyl, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIa),    -   R⁷ is not methyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IIb) or (IIc),

-   -   R⁷ is not methyl or 2-(N,N-diethylamino)ethyl;    -   when R⁷ is methyl, R⁵ is chloro, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIIa),

-   -   R⁶ is not bromo;    -   when R⁵ is chloro, R⁶ is methoxy, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IIIb):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVa):

-   -   R⁷ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVb):

-   -   R⁷ is not 2-methoxyethyl or benzyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVc):

-   -   R⁷ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVd):

-   -   R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl;    -   when each R⁵ and R⁶ is chloro, Z¹ is —OR⁷, and R³ and R⁴ combine        to form a group according to formula (IVe) or (IVf):

-   -   R⁷ is not benzyl;    -   when R⁵ is chloro, R⁶ is bromo, Z¹ is —OR⁷, and R³ and R⁴        combine to form a group according to formula (IVg), (IVh),        (IVi), (IVj), or (IVk):

-   -   R⁷ is not methyl;    -   when R⁶ is methyl,    -   each R¹ and R² is H; and    -   when R³ is H, Z¹ is —OR⁷, and each R⁵ and R⁶ is chloro,    -   R⁷ is not methyl.

4. A compound according to formula (Ib):

or a pharmaceutically acceptable salt thereof,

-   -   where    -   each of R¹ and R² is, independently, H or optionally substituted        C₁₋₃ alkyl;    -   R³ is H, halogen, cyano, optionally substituted C₁₋₆ alkyl,        optionally substituted C₁₋₃ alkoxy, or optionally substituted        amino, and R⁴ is halogen, cyano, optionally substituted C₁₋₆        alkyl, optionally substituted C₁₋₃ alkoxy, optionally        substituted amino, optionally substituted C₁₋₆ thioalkoxy, or        optionally substituted C₆₋₁₀ aryl, or R³ and R⁴, together with        the atoms to which each is attached, join to form an optionally        substituted five- or six-membered ring optionally including one        nitrogen, one sulfur, or one oxygen, where the nitrogen is        optionally substituted with R⁹;    -   each of R⁵ and R⁶ is, independently, H, optionally substituted        C₁₋₃ alkyl, optionally substituted C₁₋₃ alkoxy, halogen, or CN;    -   R⁷ is optionally substituted C₁₋₃ alkyl, optionally substituted        C₁₋₃ alkcycloalkyl, optionally substituted C₁₋₃ alkheterocyclyl,        or optionally substituted C₁₋₃ alkaryl, and R⁸ is H; or R⁷ and        R⁸, together with the atoms to which each is attached, join to        form an optionally substituted five- or six-membered ring; and    -   R⁹ is H, optionally substituted C₁₋₃ alkyl, optionally        substituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,        optionally substituted C₂₋₉ heteroaryl, optionally substituted        C₂₋₉ heterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl,        optionally substituted C₁₋₃ alkheterocyclyl, or optionally        substituted C₁₋₃ alkaryl;        where,    -   when each of R¹ and R² is H, R³ is H, R⁴ is methyl or chloro,        and each of R⁵ and R⁶ is chloro,    -   R⁷ is not methyl;    -   when each of R⁵ and R⁶ is chloro, R³ is H, and R⁴ is halogen,    -   R⁷ is not 2-amino-2-oxoethyl, 2-(N,N-diethylamino)ethyl, methyl,        or benzyl;    -   when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴ combine to form a        group according to formula (IIa):

-   -   R⁷ is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl,        2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl,        2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl,        2-(N,N-dimethylamino)-ethyl, difluoromethyl, or        2-(t-butylamino)ethyl;    -   when each R⁵ and R⁶ is bromo, and R³ and R⁴ combine to form a        group according to formula (IIa),    -   R⁷ is not methyl;    -   when each R⁵ and R⁶ is chloro, R⁸ is H, and R³ and R⁴ combine to        form a group according to formula (IIa),    -   R⁷ is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl,        2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl,        2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl,        2-pyrimidinylmethyl, imidazol-2-yl-methyl,        5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or        3-methyl-1,2,4-oxadiazol-5-yl-methyl;    -   when each R⁵ and R⁶ is chloro, R⁷ and R⁸ combine to form        —CH₂—CH₂—, and R³ and R⁴ combine to form a group according to        formula (IIa),    -   R⁹ is not ethoxycarbonyl, cyclobutylaminocarbonyl, or        cyclobutadienylaminocarbonyl;    -   when R⁵ is methoxy, R⁶ is methyl, and R³ and R⁴ combine to form        a group according to formula (IIa),    -   R⁷ is not methyl;    -   when R⁵ is chloro, R⁶ is ethyl, and R³ and R⁴ combine to form a        group according to formula (IIa),    -   R⁷ is not methyl;    -   when each R⁵ and R⁶ is chloro, and R³ and R⁴ combine to form a        group according to formula (IIb) or (IIc),

-   -   R⁷ is not methyl or 2-(N,N-diethylamino)ethyl;    -   when R⁷ is methyl, R⁵ is chloro, and R³ and R⁴ combine to form a        group according to formula (IIIa),

-   -   R⁶ is not bromo;    -   when R⁵ is chloro, R⁶ is methoxy, and R³ and R⁴ combine to form        a group according to formula (IIIb):

-   -   neither R¹ nor R² is 2-(N,N-diethylamino)ethyl;    -   when each R⁵ and R⁶ is chloro, and R³ and R⁴ combine to form a        group according to formula (IVa):

-   -   R⁷ is not 3-(N-morpholinyl)propyl, benzyl,        1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl,        2-(1-methyl-pyrrolidin-2-yl)ethyl, or        3-(N,N-diethylamino)propyl;    -   when each R⁵ and R⁶ is chloro, and R³ and R⁴ combine to form a        group according to formula (IVb):

-   -   R⁷ is not 2-methoxyethyl or benzyl;    -   when each R⁵ and R⁶ is chloro, and R³ and R⁴ combine to form a        group according to formula (IVc):

-   -   R⁷ is not 2-(N,N-diethylamino)ethyl or        3-(N,N-dimethylamino)propyl;    -   when each R⁵ and R⁶ is chloro, and R³ and R⁴ combine to form a        group according to formula (IVd):

-   -   R⁷ is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl;    -   when each R⁵ and R⁶ is chloro, and R³ and R⁴ combine to form a        group according to formula (IVe) or (IVf):

-   -   R⁷ is not benzyl;    -   when R⁵ is chloro, R⁶ is bromo, and R³ and R⁴ combine to form a        group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

-   -   R⁷ is not methyl;    -   when R⁶ is methyl,    -   each R¹ and R² is H; and    -   when R³ is H, and each R⁵ and R⁶ is chloro,    -   R⁷ is not methyl.

5. The compound of any one of embodiments 1 to 4, where R³ is H,halogen, optionally substituted C₁₋₃ alkyl, or optionally substitutedC₁₋₃ alkoxy, and R⁴ is halogen, optionally substituted C₁₋₃ alkyl,optionally substituted C₁₋₃ alkoxy, optionally substituted amino,optionally substituted C₁₋₆ thioalkyl, or optionally substituted C₆₋₁₀aryl, or R³ and R⁴, together with the atoms to which each is attached,join to form an optionally substituted five- or six-membered ringoptionally including one nitrogen, one oxygen, or one sulfur, where thenitrogen is optionally substituted with R⁹.

6. The compound of any one of embodiments 1 to 5, where R³ and R⁴,together with the atoms to which each is attached, join to form anoptionally substituted five-membered ring.

7. The compound of any one of embodiments 1 to 5, where R³ and R⁴combine to form —CH₂CH₂CH₂— group.

8. The compound of any one of embodiments 1 to 5, where R³ and R⁴,together with the atoms to which each is attached, join to form anoptionally substituted five-membered ring including one nitrogen.

9. The compound of embodiment 8, where R³ and R⁴ combine to form—N(R⁹)—CH═CH— group.

10. The compound of embodiment 9, where R⁹ is H.

11. The compounds of any one of embodiments 1 to 5, where R³ and R⁴,together with the atoms to which each is attached, join to form anoptionally substituted five-membered ring including one sulfur.

12. The compound of any one of embodiments 1 to 5, where R³ and R⁴combine to form —C(R^(13A))═C(R^(13B))—S— group, where R^(13A) is H, andR^(13B) is H or optionally substituted C₁₋₃ alkyl.

13. The compound of embodiment 12, where R^(13B) is optionallysubstituted C₁₋₃ alkyl.

14. The compound of embodiment 13, where R^(13B) is —C(O)—R^(13C), whereR^(13C) is optionally substituted C₁₋₃ alkoxy or optionally substitutedamino.

15. The compound of any one of embodiments 1 to 5, where R³ and R⁴combine to form —C(R^(13A))═C(R^(13B))—S— group, where R^(13A) is H, andR^(13B) is H or —C(O)—R^(13C), where R^(13C) is optionally substitutedC₁₋₃ alkyl, optionally substituted C₁₋₃ alkoxy, optionally substitutedamino, or optionally substituted C₂₋₉ heterocyclyl.

16. The compound of any one of embodiments 1 to 5, where R⁴ is C₁₋₃alkyl.

17. The compound of embodiment 16, where R⁴ is methyl, ethyl, orisopropyl.

18. The compound of any one of embodiments 1 to 5, where R⁴ is C₁₋₃alkoxy.

19. The compound of embodiment 18, where R⁴ is methoxy.

20. The compound of any one of embodiments 1 to 5, where R⁴ isoptionally substituted C₁₋₆ thioalkoxy.

21. The compound of embodiment 20, where R⁴ is 4-amino-4-oxobutyl.

22. The compound of any one of embodiments 1 to 5, where R⁴ isoptionally substituted amino.

23. The compound of embodiment 22, where R⁴ is methylamino.

24. The compound of any one of embodiments 1 to 5, where R⁴ is halogen.

25. The compound of embodiment 24, where R⁴ is chloro.

26. The compound of any one of embodiments 1-5 and 15-25, where R³ ishydrogen or C₁₋₃ alkyl.

27. The compound of embodiment 26, where R³ is hydrogen, methyl, orethyl.

28. The compound of any one of embodiments 1 to 5, where R³ and R⁴combine to form —X¹—X²—X³—, where

-   -   X¹ is —S—, —O—, —(CR¹⁴R¹⁵)—, —C(R¹⁶)═, —N(R⁹)—, —N═, H, or        optionally substituted C₁₋₃ alkyl; X² is absent,—(CR¹⁷R¹⁸)_(n)—,        —S—, —O—, —N═, —N(R⁹)—, —C(R¹⁹)═, ═N—, ═C(R²⁰)—, or        ═C(R²¹)—C(R²²)═;    -   X³ is —(CR¹⁴R¹⁵)—, —S—, —O—, —N(R⁹)—, ═N—, ═C(R²³)—, halogen,        optionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₆        thioalkoxy, optionally substituted C₁₋₃ alkoxy, or optionally        substituted C₆₋₁₀ aryl;    -   each R¹⁴ and R¹⁵ is, independently, H or optionally substituted        C₁₋₃ alkyl, or R¹⁴ and R¹⁵ combine to form ═O or ═S;    -   each R¹⁷ and R¹⁸ is, independently, H or optionally substituted        C₁₋₃ alkyl, or R¹⁷ and R¹⁸ combine to form ═O or ═S;    -   each R¹⁶, R¹⁹, R²⁰, R²¹, R²², and R²³ is, independently, H, or        optionally substituted C₁₋₃ alkyl; and    -   n is 1 or 2; and        where, when X² is not absent,    -   the chain of atoms —X¹—X²—X³— includes no more than one        heteroatom, the heteroatom being selected from the group        consisting of nitrogen, oxygen, and sulfur.

29. The compound of embodiment 28, where X¹ is —(CR¹⁴R¹⁵)—, —C(R¹⁶)═,—N(R⁹)—, —N═, or optionally substituted C₁₋₃ alkyl.

30. The compound of embodiment 29, where X¹ is —(CR¹⁴R¹⁵)—.

31. The compound of embodiment 30, where each R¹⁴ and R¹⁵ is H.

32. The compound of embodiment 29, where X¹ is —C(R¹⁶)═.

33. The compound of embodiment 32, where R¹⁶ is H.

34. The compound of embodiment 29, where X¹ is —N(R⁹)—.

35. The compound of embodiment 34, where R⁹ is H or optionallysubstituted C₁₋₃ alkyl.

36. The compound of embodiment 35, where R⁹ is hydrogen, methyl, orethyl.

37. The compound of embodiment 29, where X¹ is-N═.

38. The compound of embodiment 29, where X¹ is optionally substitutedC₁₋₃ alkyl.

39. The compound of any one of embodiments 28 to 37, where X² is absent,—(CH₂)_(n)—, —N(R⁹)—, —C(H)═, ═C(R²⁰)—, or ═C(H)—C(H)═.

40. The compound of embodiment 39, where X² is —C(H)═.

41. The compound of embodiment 39, where X² is —N(R⁹)—.

42. The compound of embodiment 41, where R⁹ is H.

43. The compound of embodiment 41, where R⁹ is optionally substitutedC₁₋₃ alkyl.

44. The compound of embodiment 43, where R⁹ is —C(O)—N(H)-Et.

45. The compound of embodiment 39, where X² is ═C(R²⁰)—.

46. The compound of embodiment 45, where R²⁰ is optionally substitutedC₁₋₃ alkyl.

47. The compound of embodiment 39, where X² is absent.

48. The compound of any one of embodiments 28-37 and 39-47, where X³ is—CH₂—, —S—, ═C(H)—, —N(R⁹)—, halogen, optionally substituted C₁₋₃ alkyl,optionally substituted C₁₋₃ alkoxy, optionally substituted C₁₋₆thioalkoxy, optionally substituted C₆₋₁₀ aryl.

49. The compound of embodiment 48, where X³ is —CH₂—.

50. The compound of embodiment 48, where X³ is —S—.

51. The compound of embodiment 48, where X³ is ═C(H)—.

52. The compound of embodiment 48, where X³ is —N(R⁹)—.

53. The compound of embodiment 48, where X³ is halogen, optionallysubstituted C₁₋₃ alkyl, optionally substituted C₁₋₃ alkoxy, optionallysubstituted C₁₋₆ thioalkoxy, or optionally substituted C₆₋₁₀ aryl.

54. The compound of any one of embodiments 1 to 53, where each R⁵ and R⁶is, independently, halo or optionally substituted C₁₋₃ alkyl.

55. The compound of embodiment 54, where each R⁵ and R⁶ is halo.

56. The compound of embodiment 55, where each R⁵ and R⁶ is chloro.

57. The compound of any one of embodiments 1 to 56, where R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five- or six-membered ring optionally includingone or two heteroatoms selected from nitrogen, oxygen, and sulfur.

58. The compound of any one of embodiments 1 to 56, where R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five- or six-membered saturated ring optionallyincluding one or two heteroatoms selected from nitrogen, oxygen, andsulfur.

59. The compound of any one of embodiments 1 to 56, where R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five- of six-membered ring optionally includingone or two heteroatoms selected from nitrogen and oxygen.

60. The compound of any one of embodiments 1 to 56, where R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted five-membered ring.

61. The compound of any one of embodiments 1 to 56, where the R⁷ and R⁸,together with the atoms to which each is attached, join to form anoptionally substituted saturated five-membered ring.

62. The compound of any one of embodiments 1 to 56, where the R⁷ and R⁸combine to form a —CH₂CH₂— group.

63. The compound of any one of embodiments 1 to 56, where R⁷ isoptionally substituted C₁₋₃ alkyl.

64. The compound of embodiment 63, where R⁷ is methyl.

65. The compound of embodiment 63, where R⁷ is —(CH₂)_(k)—N(R²⁴)R²⁵,where k is 2 or 3, and where each R²⁴ and R²⁵ is, independently, H oroptionally substituted C₁₋₃ alkyl.

66. The compound of embodiment 65, where k is 2.

67. The compound of embodiment 65 or 66, where each R²⁴ and R²⁵ is,independently, optionally substituted C₁₋₃ alkyl.

68. The compound of any one of embodiments 65 to 67, where each R²⁴ andR²⁵ is methyl.

69. The compound of any one of embodiments 1 to 56, where R⁷ and R⁸ forma group —Y¹—Y²—, where:

-   -   Y¹ is —(CR²⁶R²⁷)_(m)— or optionally substituted C₁₋₃ alkyl,        optionally substituted C₁₋₃ alkheterocyclyl, optionally        substituted C₁₋₃ alkcycloalkyl, or optionally substituted C₁₋₃        alkaryl; and    -   Y² is —(CR²⁶R²⁷)— or H; where each R²⁶ and R²⁷ is,        independently, H or optionally substituted C₁₋₃ alkyl; and    -   m is 1 or 2.

70. The compound of any one of embodiments 1 to 5, where Z¹ and R⁸combine to form —Z³—Y¹—Y²—, where

-   -   Z³ is —O—, —N(R¹⁰)—, —N═, —S—, or —(CR¹⁴R¹⁵)—;    -   Y¹ is —O—, —N(R¹⁰)—, —S—, —(CR²⁶R²⁷)_(m)—, —C(R²⁰)═, ═C(R²⁰)—,        ═C(R²¹)—C(R²²)═, optionally substituted C₁₋₃ alkyl, optionally        substituted C₁₋₃ alkheterocyclyl, optionally substituted C₁₋₃        alkcycloalkyl, or optionally substituted C₁₋₃ alkaryl; and    -   Y² is —O—, —S—, —N(R¹⁰)—, —(CR²⁶R²⁷)—, ═C(R²⁰)—, ═N—, or H;    -   where    -   each R²⁰, R²¹, and R²² is, independently, H or optionally        substituted C₁₋₃ alkyl; and    -   each R²⁶ and R²⁷ is, independently, H or optionally substituted        C₁₋₃ alkyl, or R²⁶ and R²⁷ combine to form ═O or ═S;    -   m is 1 or 2; and        where, when Y² is H,    -   the chain of atoms —Z³—Y¹—Y²— includes no more than two        heteroatoms, the heteroatom selected from nitrogen, oxygen, and        sulfur.

71. The compound of embodiment 70, where Z³ is —O—.

72. The compound of embodiment 69 or 71, where Y¹ is —(CR²⁶R²⁷)_(m)— oroptionally substituted C₁₋₃ alkyl, optionally substituted C₁₋₃alkheterocyclyl, optionally substituted C₁₋₃ alkcycloalkyl, oroptionally substituted C₁₋₃ alkaryl.

73. The compound of any one of embodiments 69 to 72, where Y¹ is—(CR²⁶R²⁷)_(m)— or optionally substituted C₁₋₃ alkyl.

74. The compound of any one of embodiments 69 to 73, where Y² is—(CR²⁶R²⁷)— or H.

75. The compound of any one of embodiments 69 to 74, where Y² is—(CR²⁶R²⁷)—.

76. The compound of any one of embodiments 69 to 75, where R²⁶ is H.

77. The compound of any one of embodiments 69 to 76, where R²⁷ is H.

78. The compound of any one of embodiments 69 to 77, where m is 1.

79. The compound of any one of embodiments 69 to 78, where Y¹ isoptionally substituted C₁₋₃ alkyl.

80. The compound of embodiment 79, where Y¹ is methyl.

81. The compound of embodiment 80, where Y¹ is —(CH₂)_(k)—N(R²⁴)R²⁵,where k is 2 or 3, and where each R²⁴ and R²⁵ is, independently, H oroptionally substituted C₁₋₃ alkyl.

82. The compound of embodiment 81, where k is 2.

83. The compound of embodiment 81 or 82, where each R²⁴ and R²⁵ is,independently, optionally substituted C₁₋₃ alkyl.

84. The compound of any one of embodiments 81 to 83, where each R²⁴ andR²⁵ is methyl.

85. The compound of any one of embodiments 1 to 84, where each R¹ and R²is H.

86. A compound:

or a pharmaceutically acceptable salt thereof.

87. The compound of embodiment 84 having the formula:

or a pharmaceutically acceptable salt thereof.

88. A pharmaceutical composition including the compound of any one ofembodiments 1 to 87, or a pharmaceutically acceptable salt thereof, andone or more of pharmaceutically acceptable carriers or excipients.

89. The pharmaceutical composition of embodiment 88, where thecomposition is formulated for administration orally, sublingually,buccally, transdermally, intradermally, intramuscularly, parenterally,intravenously, intra-arterially, intracranially, subcutaneously,intraorbitally, intraventricularly, intraspinally, intraperitoneally,intranasally, by inhalation, and topically.

90. The pharmaceutical composition of embodiment 89, where thecomposition is formulated for oral administration.

91. A method of treating a disorder in a mammal caused by the action ofheat shock protein 90 (Hsp90), the method including administering aneffective amount of the compound of any one of embodiments 1 to 87 or apharmaceutically acceptable salt thereof or the pharmaceuticalcomposition of embodiment 88 to the mammal.

92. The method of embodiment 91, where the disorder is aneurodegenerative disorder.

93. The method of embodiment 92, where the neurodegenerative disorder isa tauopathy.

94. The method of embodiment 92 or 93, where the neurodegenerativedisorder is Alzheimer's disease, Huntington's disease, progressivesupranuclear palsy, Parkinson's disease, Pick's disease, corticobasaldegeneration, chronic traumatic encephalopathy, traumatic brain injury,or frontotemporal dementia.

95. The method of embodiment 94, where the neurodegenerative disorder isAlzheimer's disease.

96. The method of embodiment 91, where the disorder is a proliferativedisorder.

97. The method of embodiment 96, where the proliferative disorder is acancer.

98. The method of embodiment 97, where the cancer is acute myeloidleukemia, gastrointestinal stromal tumor, gastric cancer, glioma,neuroblastoma, glioblastoma, lung cancer, lymphoma, melanoma, myeloma,non-small cell lung cancer, renal cancer, small cell lung cancer,blast-phase chronic myelogenous leukemia, leukemia, lymphoproliferativedisorder, metastatic melanoma, relapsed multiple myeloma, refractorymultiple myeloma, myeloproliferative disorders, pancreatic cancer, smallintestine cancer, or solid tumor.

99. A method of treating an infectious disease in a mammal, the methodincluding administering an effective amount of the compound of any oneof embodiments 1 to 87 or a pharmaceutically acceptable salt or thepharmaceutical composition of embodiment 88 thereof to the mammal.

100. The method of embodiment 99, where the infectious disease is aviral infection.

101. The method of embodiment 100, where the viral infection is aninfection by a virus of a family selected from the group consisting ofHerpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae,Picornaviridae, Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae,Paramoxyviridae, Bunyaviridae, Orthomoxyviridae, Filoviridae,Retroviridae, and Hepadnaviridae.

102. The method of embodiment 101, where the virus of a familyHerpesviridae is herpes simplex virus-1, herpes simplex virus-2, herpesherpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zostervirus, or Epstein-Barr virus.

103. The method of embodiment 101, where the virus of Polyomaviridaefamily is SV40.

104. The method of embodiment 101, where the virus of Poxviridae familyis vaccinia virus.

105. The method of embodiment 101, where the virus of Reoviridae familyis rotavirus.

106. The method of embodiment 101, where the virus of Birnaviridaefamily is infectious bursal disease virus.

107. The method of embodiment 101, where the virus of Picornaviridaefamily is poliovirus, rhinovirus, or coxsackievirus.

108. The method of embodiment 101, where the virus of Flaviviridaefamily is hepatitis C virus or dengue virus.

109. The method of embodiment 101, where the virus of Arenaviridaefamily is lymphocytic choriomeningitis virus.

110. The method of embodiment 101, where the virus of Hepeviridae familyis Hepatitis E virus.

111. The method of embodiment 101, where the virus of Rhabdoviridaefamily is vesicular stomatitis virus.

112. The method of embodiment 101, where the virus of Paramoxyviridaefamily is human parainfluenza virus 2, human parainfluenza virus 3, SV5,SV41, measles virus, or Sendai virus.

113. The method of embodiment 101, where the virus of Bunyaviridaefamily is La Crosse virus.

114. The method of embodiment 101, where the virus of Orthomoxyviridaefamily is influenza A virus.

115. The method of embodiment 101, where the virus of Filoviridae familyis Ebola virus.

116. The method of embodiment 101, where the virus of Retroviridaefamily is HTLV1 or HIV1.

117. The method of embodiment 101, where the virus of Hepadnaviridaefamily is hepatitis B virus.

118. The method of embodiment 99, where the infectious disease is afungal infection.

119. The method of embodiment 118, where the fungal infection is aCandida albicans infection, an Aspergillus fumigates infection, orPneumocystis jiroveci infection.

120. The method of embodiment 99, where the infectious disease is abacterial infection.

121. The method of embodiment 120, where the bacterial infection is amycobacteria infection or anthrax infection.

122. The method of embodiment 120, where the bacterial infection is abacterial pneumonia.

123. The method of embodiment 91, where the disorder an inflammatory orautoimmune disease.

124. The method of embodiment 123, where the inflammatory or autoimmunedisease is rheumatoid arthritis, systemic lupus erythermatosus, orasthma.

125. The method of embodiment 91, where the disorder is a cardiovasculardisease.

126. The method of embodiment 125, where the cardiovascular disease isatherosclerosis or cardiomyopathy.

127. The method of embodiment 91, where the disorder is an allergy.

128. The method of any one of embodiments 91 to 127, where the compoundis administered orally, sublingually, buccally, transdermally,intradermally, intramuscularly, parenterally, intravenously,intra-arterially, intracranially, subcutaneously, intraorbitally,intraventricularly, intraspinally, intraperitoneally, intranasally, byinhalation, and topically.

129. The method of embodiment 128, where the compound is administeredorally.

130. The method of any one of embodiments 91 to 129, where the mammal ishuman.

131. The method of any one of embodiments 91 to 130, where the compoundis administered orally, sublingually, buccally, transdermally,intradermally, intramuscularly, parenterally, intravenously,intra-arterially, intracranially, subcutaneously, intraorbitally,intraventricularly, intraspinally, intraperitoneally, intranasally, byinhalation, and topically.

132. The method of embodiment 131, where the compound is administeredorally.

133. The method of any one of embodiments 91 to 132, where the mammal ishuman.

134. A compound for use in treating a disorder in a mammal caused by theaction of heat shock protein 90 (Hsp90), where the compound is thecompound of any one of embodiments 1 to 87 or a pharmaceuticallyacceptable salt thereof.

135. The compound of embodiment 134, where the disorder is aneurodegenerative disorder.

136. The compound of embodiment 135, where the neurodegenerativedisorder is a tauopathy.

137. The compound of embodiment 134 or 135, where the neurodegenerativedisorder is Alzheimer's disease, Huntington's disease, progressivesupranuclear palsy, Parkinson's disease, Pick's disease, corticobasaldegeneration, chronic traumatic encephalopathy, traumatic brain injury,or frontotemporal dementia.

138. The compound of embodiment 137, where the neurodegenerativedisorder is Alzheimer's disease.

139. The compound of embodiment 134, where the disorder is aproliferative disorder.

140. The compound of embodiment 139, where the proliferative disorder isa cancer.

141. The compound of embodiment 140, where the cancer is acute myeloidleukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma,lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer,renal cancer, small cell lung cancer, blast-phase chronic myelogenousleukemia, leukemia, lymphoproliferative disorder, metastatic melanoma,relapsed multiple myeloma, refractory multiple myeloma,myeloproliferative disorders, pancreatic cancer, small intestine cancer,or solid tumor.

142. The compound of embodiment 134, where the disorder is an infectiousdisease.

143. The compound of embodiment 142, where the infectious disease is aviral infection.

144. The compound of embodiment 143, where the viral infection is aninfection by a virus of a family selected from the group consisting ofHerpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae,Picornaviridae, Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae,Paramoxyviridae, Bunyaviridae, Orthomoxyviridae, Filoviridae,Retroviridae, and Hepadnaviridae.

145. The compound of embodiment 144, where the virus of a familyHerpesviridae is herpes simplex virus-1, herpes simplex virus-2, herpesherpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zostervirus, or Epstein-Barr virus.

146. The compound of embodiment 144, where the virus of Polyomaviridaefamily is SV40.

147. The compound of embodiment 144, where the virus of Poxviridaefamily is vaccinia virus.

148. The compound of embodiment 144, where the virus of Reoviridaefamily is rotavirus.

149. The compound of embodiment 144, where the virus of Birnaviridaefamily is infectious bursal disease virus.

150. The compound of embodiment 144, where the virus of Picornaviridaefamily is poliovirus, rhinovirus, or coxsackievirus.

141. The compound of embodiment 144, where the virus of Flaviviridaefamily is hepatitis C virus or dengue virus.

152. The compound of embodiment 144, where the virus of Arenaviridaefamily is lymphocytic choriomeningitis virus.

153. The compound of embodiment 144, where the virus of Hepeviridaefamily is Hepatitis E virus.

154. The compound of embodiment 144, where the virus of Rhabdoviridaefamily is vesicular stomatitis virus.

155. The compound of embodiment 144, where the virus of Paramoxyviridaefamily is human parainfluenza virus 2, human parainfluenza virus 3, SV5,SV41, measles virus, or Sendai virus.

156. The compound of embodiment 144, where the virus of Bunyaviridaefamily is La Crosse virus.

157. The compound of embodiment 144, where the virus of Orthomoxyviridaefamily is influenza A virus.

158. The compound of embodiment 144, where the virus of Filoviridaefamily is Ebola virus.

159. The compound of embodiment 144, where the virus of Retroviridaefamily is HTLV1 or HIV1.

160. The compound of embodiment 144, where the virus of Hepadnaviridaefamily is hepatitis B virus.

161. The compound of embodiment 134, where the infectious disease is afungal infection.

162. The compound of embodiment 161, where the fungal infection is aCandida albicans infection, an Aspergillus fumigates infection, orPneumocystis jiroveci infection.

163. The compound of embodiment 134, where the infectious disease is abacterial infection.

165. The compound of embodiment 163, where the bacterial infection is amycobacteria infection or anthrax infection.

166. The compound of embodiment 163, where the bacterial infection is abacterial pneumonia.

167. The compound of embodiment 134, where the disorder an inflammatoryor autoimmune disease.

168. The compound of embodiment 167, where the inflammatory orautoimmune disease is rheumatoid arthritis, systemic lupuserythermatosus, or asthma.

169. The compound of embodiment 134, where the disorder is acardiovascular disease.

170. The compound of embodiment 169, where the cardiovascular disease isatherosclerosis or cardiomyopathy.

171. The compound of embodiment 170, where the disorder is an allergy.

172. Use of a compound in the manufacture of a medicament for treating adisorder in a mammal caused by the action of heat shock protein 90(Hsp90), where the compound is the compound of any one of embodiments 1to 87 or a pharmaceutically acceptable salt thereof.

173. Use of a compound for treating a disorder in a mammal caused by theaction of heat shock protein 90 (Hsp90), where the compound is thecompound of any one of embodiments 1 to 87 or a pharmaceuticallyacceptable salt thereof.

174. The use of embodiment 172 or 173, where the disorder is aneurodegenerative disorder.

175. The use of embodiment 174, where the neurodegenerative disorder isa tauopathy.

176. The use of embodiment 174 or 175, where the neurodegenerativedisorder is Alzheimer's disease, Huntington's disease, progressivesupranuclear palsy, Parkinson's disease, Pick's disease, corticobasaldegeneration, chronic traumatic encephalopathy, traumatic brain injury,or frontotemporal dementia.

177. The use of embodiment 176, where the neurodegenerative disorder isAlzheimer's disease.

178. The use of embodiment 172 or 173, where the disorder is aproliferative disorder.

179. The use of embodiment 178, where the proliferative disorder is acancer.

180. The use of embodiment 179, where the cancer is acute myeloidleukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma,lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer,renal cancer, small cell lung cancer, blast-phase chronic myelogenousleukemia, leukemia, lymphoproliferative disorder, metastatic melanoma,relapsed multiple myeloma, refractory multiple myeloma,myeloproliferative disorders, pancreatic cancer, small intestine cancer,or solid tumor.

181. Use of a compound for treating, or in the manufacture of amedicament for treating, an infectious disease, where the compound isthe compound of any one of embodiments 1 to 87.

182. The use of embodiment 181, where the infectious disease is a viralinfection.

183. The use of embodiment 182, where the viral infection is aninfection by a virus of a family selected from the group consisting ofHerpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae,Picornaviridae, Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae,Paramoxyviridae, Bunyaviridae, Orthomoxyviridae, Filoviridae,Retroviridae, and Hepadnaviridae.

184. The use of embodiment 183, where the virus of a familyHerpesviridae is herpes simplex virus-1, herpes simplex virus-2, herpesherpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zostervirus, or Epstein-Barr virus.

185. The use of embodiment 183, where the virus of Polyomaviridae familyis SV40.

186. The use of embodiment 183, where the virus of Poxviridae family isvaccinia virus.

187. The use of embodiment 183, where the virus of Reoviridae family isrotavirus.

188. The use of embodiment 183, where the virus of Birnaviridae familyis infectious bursal disease virus.

189. The use of embodiment 183, where the virus of Picornaviridae familyis poliovirus, rhinovirus, or coxsackievirus.

190. The use of embodiment 183, where the virus of Flaviviridae familyis hepatitis C virus or dengue virus.

191. The use of embodiment 183, where the virus of Arenaviridae familyis lymphocytic choriomeningitis virus.

192. The use of embodiment 183, where the virus of Hepeviridae family isHepatitis E virus.

193. The use of embodiment 183, where the virus of Rhabdoviridae familyis vesicular stomatitis virus.

194. The use of embodiment 183, where the virus of Paramoxyviridaefamily is human parainfluenza virus 2, human parainfluenza virus 3, SV5,SV41, measles virus, or Sendai virus.

195. The use of embodiment 183, where the virus of Bunyaviridae familyis La Crosse virus.

196. The use of embodiment 183, where the virus of Orthomoxyviridaefamily is influenza A virus.

197. The use of embodiment 183, where the virus of Filoviridae family isEbola virus.

198. The use of embodiment 183, where the virus of Retroviridae familyis HTLV1 or HIV1.

199. The use of embodiment 183, where the virus of Hepadnaviridae familyis hepatitis B virus.

200. The use of embodiment 172 or 173, where the infectious disease is afungal infection.

201. The use of embodiment 200, where the fungal infection is a Candidaalbicans infection, an Aspergillus fumigates infection, or Pneumocystisjiroveci infection.

202. The use of embodiment 172 or 173, where the infectious disease is abacterial infection.

203. The use of embodiment 202, where the bacterial infection is amycobacteria infection or anthrax infection.

204. The use of embodiment 203, where the bacterial infection is abacterial pneumonia.

205. The use of embodiment 172 or 173, where the disorder aninflammatory or autoimmune disease.

206. The use of embodiment 205, where the inflammatory or autoimmunedisease is rheumatoid arthritis, systemic lupus erythermatosus, orasthma.

207. The use of embodiment 172 or 173, where the disorder is acardiovascular disease.

208. The use of embodiment 207, where the cardiovascular disease isatherosclerosis cardiomyopathy.

209. The use of embodiment 172 or 173, where the disorder is an allergy.

210. The compound of any one of embodiments 134 to 171 or the use of anyone of embodiments 172 to

209, where the compound is formulated for administration by a routeselected from the group consisting of oral, sublingual, buccal,transdermal, intradermal, intramuscular, parenteral, intravenous,intra-arterial, intracranial, subcutaneous, intraorbital,intraventricular, intraspinal, intraperitoneal, intranasal, byinhalation, and topical.

211. The compound or the use of embodiment 128, where the compound isformulated for oral administration.

212. A method of inhibiting Hsp90, the method including contacting acell with the compound of any one of embodiments 1 to 87 or apharmaceutically acceptable salt thereof.

213. The method of embodiment 212, where the cell is in vitro.

214. A compound for use in inhibiting Hsp90, where the compound is thecompound of any one of embodiments 1 to 87 or a pharmaceuticallyacceptable salt thereof.

215. Use of a compound for inhibiting Hsp90, where the compound is thecompound of any one of embodiments 1 to 87 or a pharmaceuticallyacceptable salt thereof.

216. A kit including:

-   -   (i) the pharmaceutical composition of any one of embodiments 88        to 90; and    -   (ii) instructions for use of the pharmaceutical compositions        of (i) to treat a disorder in a mammal caused by the action of        Hsp90.

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are in the claims

1-17. (canceled)
 18. A compound having the formula:

or a pharmaceutically acceptable salt thereof.
 19. A compound having theformula:

or a pharmaceutically acceptable salt thereof.
 20. A compound having theformula:

or a pharmaceutically acceptable salt thereof.
 21. A pharmaceuticalcomposition comprising the compound of claim 18, or a pharmaceuticallyacceptable salt thereof, and one or more of pharmaceutically acceptablecarriers or excipients. 22-23. (canceled)
 24. A method of treating adisorder in a mammal caused by the action of heat shock protein 90(Hsp90), said method comprising administering an effective amount of thecompound of claim 18 or a pharmaceutically acceptable salt thereof tosaid mammal. 25-26. (canceled)
 27. The method of claim 24, wherein saiddisorder is a neurodegenerative disorder selected from Alzheimer'sdisease, Huntington's disease, progressive supranuclear palsy,Parkinson's disease, Pick's disease, corticobasal degeneration, chronictraumatic encephalopathy, traumatic brain injury, and frontotemporaldementia.
 28. The method of claim 27, wherein said neurodegenerativedisorder is Alzheimer's disease. 29-43. (canceled)
 44. A method ofinhibiting Hsp90, said method comprising contacting a cell with thecompound of claim 18 or a pharmaceutically acceptable salt thereof. 45.(canceled)
 46. A kit comprising: (i) the pharmaceutical composition ofclaim 21; and (ii) instructions for use of the pharmaceuticalcompositions of (i) to treat a disorder in a mammal caused by the actionof Hsp90.
 47. A pharmaceutical composition comprising the compound ofclaim 19, or a pharmaceutically acceptable salt thereof, and one or moreof pharmaceutically acceptable carriers or excipients.
 48. A method oftreating a disorder in a mammal caused by the action of Hsp90, saidmethod comprising administering an effective amount of the compound ofclaim 19 or a pharmaceutically acceptable salt thereof to said mammal.49. The method of claim 48, wherein said disorder is a neurodegenerativedisorder selected from Alzheimer's disease, Huntington's disease,progressive supranuclear palsy, Parkinson's disease, Pick's disease,corticobasal degeneration, chronic traumatic encephalopathy, traumaticbrain injury, and frontotemporal dementia.
 50. The method of claim 49,wherein said neurodegenerative disorder is Alzheimer's disease.
 51. Amethod of inhibiting Hsp90, said method comprising contacting a cellwith the compound of claim 19 or a pharmaceutically acceptable saltthereof.
 52. A kit comprising: (i) the pharmaceutical composition ofclaim 47; and (ii) instructions for use of the pharmaceuticalcompositions of (i) to treat a disorder in a mammal caused by the actionof Hsp90.
 53. A pharmaceutical composition comprising the compound ofclaim 20, or a pharmaceutically acceptable salt thereof, and one or moreof pharmaceutically acceptable carriers or excipients.
 54. A method oftreating a disorder in a mammal caused by the action of Hsp90, saidmethod comprising administering an effective amount of the compound ofclaim 20 or a pharmaceutically acceptable salt thereof to said mammal.55. The method of claim 54, wherein said disorder is a neurodegenerativedisorder selected from Alzheimer's disease, Huntington's disease,progressive supranuclear palsy, Parkinson's disease, Pick's disease,corticobasal degeneration, chronic traumatic encephalopathy, traumaticbrain injury, and frontotemporal dementia.
 56. The method of claim 55,wherein said neurodegenerative disorder is Alzheimer's disease.
 57. Amethod of inhibiting Hsp90, said method comprising contacting a cellwith the compound of claim 20 or a pharmaceutically acceptable saltthereof.
 58. A kit comprising: (i) the pharmaceutical composition ofclaim 53; and (ii) instructions for use of the pharmaceuticalcompositions of (i) to treat a disorder in a mammal caused by the actionof Hsp90.